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Quorum sensing inhibitors as antipathogens: biotechnological applications
Accepted Manuscript Quorum sensing inhibitors as antipathogens: biotechnological applications
Vipin Chandra Kalia, Sanjay K.S. Patel, Yun Chan Kang, JungKul Lee PII: DOI: Reference:
S0734-9750(18)30190-3 https://doi.org/10.1016/j.biotechadv.2018.11.006 JBA 7317
To appear in:
Biotechnology Advances
Received date: Revised date: Accepted date:
10 May 2018 19 October 2018 18 November 2018
Please cite this article as: Vipin Chandra Kalia, Sanjay K.S. Patel, Yun Chan Kang, JungKul Lee , Quorum sensing inhibitors as antipathogens: biotechnological applications. Jba (2018), https://doi.org/10.1016/j.biotechadv.2018.11.006
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ACCEPTED MANUSCRIPT Quorum Sensing Inhibitors as Antipathogens: Biotechnological Applications
Vipin Chandra Kaliaa*, Sanjay K. S. Patel a, Yun Chan Kang b, Jung-Kul Lee a*
Department of Chemical Engineering, Konkuk University, Seoul 05029, Republic of Korea
b
Department of Materials Science and Engineering, Korea University, Anam-Dong,
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a
Corresponding authors:
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*
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Seongbuk-Gu, Seoul 02841, Republic of Korea
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E-mail: [email protected] (V.C. Kalia) or [email protected] (J-K. Lee)
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Abstract The mechanisms through which microbes communicate using signal molecules has inspired a great deal of research. Microbes use this exchange of information, known as quorum sensing (QS), to initiate and perpetuate infectious diseases in eukaryotic organisms, evading the
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eukaryotic defense system by multiplying and expressing their pathogenicity through QS
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regulation. The major issue to arise from such networks is increased bacterial resistance to
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antibiotics, resulting from QS-dependent mediation of the formation of biofilm, the induction of efflux pumps, and the production of antibiotics. QS inhibitors (QSIs) of diverse origins
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have been shown to act as potential antipathogens. In this review, we focus on the use of QSIs to counter diseases in humans as well as plants and animals of economic importance.
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We also discuss the challenges encountered in the potential applications of QSIs.
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pathogens, quorum sensing.
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Keywords: antipathogens, aquaculture, biofilm, human health, infectious diseases, inhibitors,
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Abbreviations Acylhomoserine lactone
AI
Autoinducer
AIP
Autoinducing peptide
DSF
Diffusible signal factor
HSL
Homoserine lactone
MBR
Membrane bioreactor
MIC
Minimum inhibitory concentration
PHAs
Polyhydroxyalkanoates
PQS
Pseudomonas quinolone signal
QS
Quorum sensing
QSI
Quorum sensing inhibitor
QSS
Quorum sensing system
C4HSL
N-butanoyl-L-HSL
C6HSL
N-hexanoyl-L-HSL
C7HSL
N-heptanoyl-L-HSL
C8HSL
N-octanoyl-L-HSL
C12HSL
N-dodecanoyl-L-HSL
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N-(3-hydroxyhexanoyl)-L-HSL
3OC6HSL
N-(3-oxohexanoyl)-L-HSL
3OC8HSL
N-(3-oxooctanoyl)-L-HSL
3OC10HSL
N-(3-oxodecanoyl)-L-HSL
3OC12HSL
N-(3-oxododecanoyl)-L-HSL
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OHC6HSL
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AHL
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1. Introduction Bacteria can exist as free-living forms or in association with other living organisms. Such symbiotic relationships are beneficial. However, pathogenic associations involving bacteria and humans and economically important plants and animals are a major cause of concern for
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their tendency to impose heavy economic losses. In humans, pathogenic bacteria lead to
people
are
reported
to
die
annually
due
to
infectious
diseases
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million
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infectious diseases that result in high rates of morbidity and mortality. In fact, nearly 5.7
(http://www.who.int/en/news-room/fact-sheets/detail/the-top-10-causes-of-death). Given that
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65% to 80% of these infections are caused by biofilm-forming bacteria, biofilms have become an obvious drug target (Grandclément et al., 2016; Lebeaux et al., 2013; Lewis,
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2007). Biofilms are formed by bacteria via a cell density-dependent phenomenon known as quorum sensing (QS) (Miller and Bassler, 2001). Bacteria found in QS-mediated biofilms
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have been reported to tolerate up to 1000 times higher concentrations of antibiotics in
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comparison to their planktonic counterparts (Olsen, 2015). Antibiotic tolerance was shown to occur in Pseudomonas aeruginosa PAO1 through the induction of the QS regulator VqsM,
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which in turn mediates the expression of an antibiotic resistance regulator, nfxB. Here, expression of the mexC-mexD-oprJ operon enabled bacteria to tolerate kanamycin,
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tetracycline, and quinolones (Liang et al., 2014; Poole et al., 1996). Enhancement of biofilm formation and antibiotic tolerance in P. aeruginosa has been shown to result from the release of extracellular DNA, a consequence of programmed cell death mediated by the QSregulated excretion of 2-N-heptyl-4-hydroxyquinoline-N-oxide molecule. Therefore, the release of this molecule is beneficial to the surviving cell population (Hazan et al., 2016). Transcriptomic
studies
on
the
QS
transcription
regulator
MvfR
(PqsR)
in P.
aeruginosa PA14 have shown that the QS-mediated expression of the enzymes - peroxidases
ACCEPTED MANUSCRIPT shielded bacteria from β-lactam antibiotics and reactive oxygen species (H2O2) (Maura et al., 2016). In addition, it was reported that antibiotics such as levofloxacin or meropenem are responsible for the over-expression of efflux pumps, stimulating QS-mediated biofilm formation that enables Acinetobacter baumannii to tolerate higher concentrations of antibiotics (He et al., 2015). In view of the multi-dimensional role of QS in increasing
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antibiotic tolerance in bacteria, strategies are being developed to reduce bacterial
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pathogenicity using QS inhibitors (QSIs) (Defoirdt, 2018).
1.1 Quorum sensing
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Bacteria communicate with one another through the QS system (QSS) to perform certain societal functions collectively at high cell densities. These processes prove costly and
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ineffective when bacterial densities are low (Heilmann et al., 2015). A wide range of microbes use the QSS as a defense mechanism by producing antibiotics, undergoing
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sporulation, forming biofilms, and even expressing bioluminescence (Castang et al., 2004;
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Hammer and Bassler, 2003; Liu et al., 2015; Miller and Bassler, 2001). Environmental stimuli including the nutrient profiles of media (especially limitations in nitrogen and iron,
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and concentrations of phosphate, magnesium, and amino acids), pH, temperature, osmolarity, glucose and oxygen availability, and redox state have all been reported to influence the
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expression of QS-mediated and QS regulatory genes (Bazire et al., 2005; Bollinger et al., 2001; DeLisa et al., 2001; Duan and Surette, 2007; Frederix and Downie, 2011; Hasegawa et al., 2005; Kim et al., 2005; McGowan et al., 2005; Sonck et al., 2009; Surette and Bassler, 1999; Wagner et al., 2003; Yates et al., 2002). Certain bacteria exploit the QSS to produce an arsenal that attacks other organisms through heightened expression of virulence and pathogenicity factors. Expression of pathogenicity and virulence via the QSS broadly involves the following steps: (i) synthesis of QS signal molecules; (ii) release of signal
ACCEPTED MANUSCRIPT molecules into the milieu; (iii) sensing and binding of the signal molecules to the membrane receptors at high cell density, (iv) retrieval of the receptor-signal complex by the cell and its binding to the promoter region; and (v) transcription of genes responsible for pathogenicity (Fig. 1) (Deng et al., 2011; Durán et al., 2016; Jayaraman and Wood, 2008). QS operates through the synthesis of small molecules called autoinducers (AIs) (Papenfort
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and Bassler, 2016). Autoinducing peptides (AIPs) have been shown to regulate QS in Gram-
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positive bacteria, such as various species of Clostridium, Enterococcus, Bacillus,
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Streptococcus, Staphylococcus, and Listeria (Koul et al., 2016; Monnet et al., 2016). On the other hand, Gram-negative bacteria such as different species of Acidothiobacillus,
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Acinetobacter, Burkholderia, Escherichia, Pseudomonas, Vibrio, and Yersinia employ another group of AIs: the acylhomoserine lactones (AHLs) (Koul et al., 2016; Schuster et al.,
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2013). In addition to these two major groups of AIs, the use of a wide range of signaling molecules by bacteria have been reported, including the following: (i) fatty acids
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by Burkholderia spp., Ralstonia solanacearum, Xanthomonas spp., and Xylella spp. (Flavier
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et al., 1997; Zhou et al., 2017); (ii) ketones by Legionella spp. and Vibrio spp. (Tiaden and Hilbi, 2012); (iii) epinephrine, norepinephrine, and
AI-3 by enterohemorrhagic
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bacteria (Kendall and Sperandio, 2007); (iv) Pseudomonas quinolone signal (PQS) (quinolones and diketopiperazines) by P. aeruginosa (Heeb et al., 2011; Pesci et al., 1999);
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and (v) pheromones and short peptides by Bacilli and Gram-positive bacteria (Grossman, 1995; Ng and Bassler, 2009). Autoinducer-2 (AI-2), a furanosyl borate diester, has been reported to be employed by both Gram-positive and Gram-negative bacteria for regulating their QS activities (Chen et al., 2002). Evidence of the occurrence of QS in extremophiles has been rather scarce: (i) the hyperthermophile Thermotoga maritima uses peptide-based QS (Johnson et al., 2005); (ii) the QSS of archaea and Oceanithermus profundus of phylum Deinococcus-Thermus is regulated by AI-2 signals (Kaur et al., 2018; Sun et al., 2004); and
ACCEPTED MANUSCRIPT (iii) haloalkaliphiles such as Natronococcus occultus (Paggi et al., 2003) and Halomonas (Llamas et al., 2005; Tahrioui et al., 2011) use AHL-based QS. It has been observed that most bacteria conduct QS through a single signal synthase gene and its corresponding transcription regulator. However, the presence of multiple QSS has been recorded among Bacillus, Clostridium, Pseudomonas, Sinorhizobium, Streptococcus, and Vibrio spp. (Kalia et
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al., 2014; Koul et al., 2016; Lee and Zhang, 2015; Plener et al., 2015). These multiple
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systems work in either a hierarchical manner or as a network (Miller et al. 2002; Mok et al.
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2003; Yarwood and Schlievert, 2003).
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1.2 Quorum sensing inhibition
Bacteria that can recognize this QS communication have developed the capacity to
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interfere with it at different stages. A wide range of QSIs have been reported to act by different mechanisms: (i) inhibiting the synthesis of signal molecules; (ii) enzymatically
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degrading the signal molecules; (iii) competing with signal molecules for binding to receptor
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sites; (iv) interfering with the binding of signal molecules to gene promoters and inhibiting gene expression; and (v) scavenging of AIs by antibodies and macromolecules such as
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cyclodextrins (Kalia, 2013; Kalia and Purohit, 2011; Kato et al., 2006, 2007; Morohoshi et al., 2013; Park et al., 2007). Enzymes produced by a wide range of prokaryotes with an
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ability to degrade QS signal molecules (AHLs in particular) include lactonases, oxidoreductases, acylases, and phosphotriesterase-like lactonases, (Fetzner, 2015), whereas oxidoreductases target AI-2 (Dong et al., 2000; Weiland-Bräuer et al., 2016). A variety of small molecules including certain intermediates of the AHL biosynthesis route, noncognate AHLs, and dicyclic peptides have also been reported to act as QSIs (Bauer and Robinson, 2002; Givskov et al., 1996). A wide variety of plants are known to synthesize QSIs that either degrade QS signals or compete for signal receptors (Brackman et al., 2008; Ni et al.,
ACCEPTED MANUSCRIPT 2008; Teplitski et al., 2011; Vattem et al., 2007). Extracts from different parts of Emblica officinalis (medicinal plant), Medicago truncatula, Curcuma longa, cinnamon, grape fruit, and other edible plants and fruits have been reported to be effective against infections caused by plant pathogens (Brackman et al., 2008; Gao et al., 2003; Girennavar et al., 2008; Kalia, 2103; Mathesius et al., 2003; Ni et al., 2008; Niu and Gilberts, 2004; Niu et al., 2006;
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Rudrappa and Bais, 2008). Bioactive molecules produced naturally by marine organisms and
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fungi and chemically synthesized compounds and antibodies have also been reported to act
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as QSIs (Certner and Vollmer, 2018; Defoirdt et al., 2012; Delago et al., 2016; Ding et al., 2017; Grandclément et al., 2016; Helman and Chernin, 2015; Huma et al., 2011; Joshi et al.,
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2016; Kalia, 2013; Kalia and Purohit, 2011; Reuter et al., 2016; Yang et al., 2018). An interesting feature of QSIs is that they operate at lower than minimum inhibitory
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concentration (MIC). Thus, bacteria do not perceive threats to their survival and continue to grow without causing disease (Kalia, 2013; Kalia and Purohit, 2011). QS-mediated
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production of violacein dye by Chromobacterium violaceum CV026 was completely blocked
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by 10-3 M of synthetic QSI-furanone-{5-hydroxy-3-[(1R)-1-hydroxy-2,2-dimethylpropyl]-4methylfuran-2(5H)-one}. However, at a higher concentration (10-2 M), the QSI proved toxic
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and resulted in growth inhibition (Martinelli et al., 2004). Evidence in support of the bacterial potential to develop resistance against QSIs will be presented in a subsequent section.
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QSIs have been widely investigated and show great potential for biotechnological applications (Table 1). Most studies have been conducted on a small scale, largely using biosensor strains; strategies for commercial applications must also be developed. Here, we focus on the potential biotechnological applications of QSIs in aquaculture, plants, and health care by reviewing field studies carried out in these areas primarily over the last four to five years.
ACCEPTED MANUSCRIPT 2. Aquaculture The aquaculture industry is among the fastest growing sectors of food production worldwide. It is severely impacted by pathogens, which cause infectious diseases leading to huge economic losses. The most prevalent aquatic pathogens, which kill fish, prawns, shrimp, and mollusks, are Vibrio spp. and Aeromonas spp. (Baker-Austin and Oliver, 2018;
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Fuente et al., 2015; Niu et al., 2014; Zhao et al., 2015). These pathogens also damage host
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tissues in shrimp and fish by producing lytic enzymes such as hemolysins, proteases,
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chitinases and lipases, (Defoirdt et al., 2010a; Sun et al., 2007; Teo et al., 2003a,b). Bacteria attack these animals via QS-mediated pathogenicity (Defoirdt, 2013a; Defoirdt et al., 2011a;
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Garde et al., 2010; Vanmaele et al., 2015; Yildiz and Visick, 2009). Apart from antibiotics, numerous treatment strategies have been deemed useful in aquaculture, including probiotics,
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prebiotics, and immunostimulants (Ganguly et al., 2010). However, studies are required to discover and test QSIs which can help minimize economic losses on the commercial scale.
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QSIs administered to aquatic organisms as feed supplements are gaining interest to confer
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protection against pathogens (Defoirdt, 2013a,b; Kalia and Kumar, 2015).
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2.1 QSIs of microbial origin
QSSs operate through AHLs whose specificity depends upon the length of the acyl side
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chain. AHLs that differ even slightly from the cognate AHLs cannot function effectively and may even prove inhibitory (Fuqua et al., 2001). In Aeromonas species, short-chain AHLs are dominant in regulating QS. However, long-chain AHLs can reduce virulence factors in Aeromonas hydrophila and A. salmonicida. Interestingly, burbot (Lota lota) larvae can be spared from mortality caused by these organisms through QS regulation by long-chain AHLs such as N-tetradecanoyl-L-homoserine lactone (HSL) (Table 1) (Natrah et al., 2012). One of the most extensively studied mechanisms for degrading AHL signals and preventing QS-
ACCEPTED MANUSCRIPT mediated pathogenic diseases is the use of AHL lactonases and AHL acylases (Kalia, 2013; Kalia and Purohit, 2011). The lactonase enzymes act by opening the lactone ring, whereas acylases act by cleaving the side chain of the AHL molecule. AHL lactonases have been widely reported to occur in Bacillus species (Defoirdt et al., 2011b; Kumar et al., 2013; Zhou et al., 2016). However, few organisms have been reported to possess enzymes presenting
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both activities, such as Deinococcus radiodurans R1, Photorhabdus luminescens subsp.
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laumondii TTO1, and Hyphomonas neptunium ATCC 15444 (Kalia et al., 2011; Kalia,
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2014). Lactone degrading bacteria enriched from the gut microbiome of the Penaeus vannamei shrimp helped improve survival during the first feeding in larvae of the turbot, maximus L.
(Tinh
et
al.,
2008).
Labrenzia
alexandrii,
an
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Scophthalmus
alphaproteobacterium, could degrade the QS signal molecules C6HSL, 3OC6HSL and
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OHC6HSL via its lactonase activity. Labrenzia sp. BM1 can be applied as a biocontrol agent in aquaculture to protect fish from pathogens (Ghani et al., 2014). These studies support the
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possibility of using QSIs as non-antibiotic-based novel strategies to counteract the high
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mortality rates reported in commercial scale production of marine fish. Oral administration of purified lactonase obtained from Bacillus sp. to zebrafish
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significantly reduced infection caused by A. hydrophila. The lactonase enzyme was also found to be stable in the presence of digestive enzymes, thus providing an easy and efficient
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strategy for preventing infections in fishes (Table 1) (Cao et al., 2012; Chu et al., 2014). The use of Bacillus sp. was shown to be instrumental in enhancing the survival of gnotobiotic brine shrimp (Artemia) during Vibrio campbellii infection. Here, Bacillus acted by enhancing the innate immunity of the shrimp and reducing the activities of Vibrio (Niu et al., 2014). A fish intestine-inhabiting bacterium, Flaviramulus ichthyoenteri Th78T, was also reported to exhibit QSI activity, which can be attributed to the expression of AHL lactonase. This
ACCEPTED MANUSCRIPT bacterial species can be considered to have a probiotic potential because of its ability to survive in the intestine by utilizing various available nutrients (Zhang et al., 2015). Polymers of short-chain fatty acids such as β-hydroxybutyrate are produced by diverse bacteria under environmental stress conditions (Kumar et al., 2013; Singh (M) et al., 2009). Recent studies have reported the biocontrol properties of these biomolecules (Radivojevic et
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al., 2016; Ray and Kalia, 2017). The use of polyhydroxybutyrate (PHB) and its polymer is
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reported to be effective for controlling V. campbellii infections in Artemia franciscana at 100
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mM (Table 1) (Defoirdt et al., 2007a). PHB addition to Artemia culture water at 1000 mg/L provided complete protection against Vibrio infections (Defoirdt et al., 2007a). This PHB
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effect was attributed to its degradation products, such as fatty acids, which may have been generated in the gut of starving Artemia nauplii. At present, the use of this fatty acid and its
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polymer as a protective agent is not economical (Defoirdt et al., 2007a). Enrichment cultures from activated sludge were shown to contain PHB-accumulating (32% of cell dry weight)
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organisms, which were phylogenetically close to Brachymonas dentrificans. This study
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further supported the use of PHB for protecting Artemia nauplii from V. campbellii infections (Halet et al., 2007). The concept was further developed by enriching bacteria that degrade
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AHLs and produce PHB (Dang et al., 2009; Kumar et al., 2013). A positive correlation was established between the survival of Artemia during Vibrio harveyi infection and PHB-
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accumulating organisms identified as Bacillus sp., Bacillus circulans, and Vibrio sp. It was proposed that bacteria which can degrade AHL and produce PHB can be exploited for controlling bacterial infections (Dang et al., 2009). To support the role of PHB degradation products as biocontrol agents, PHB depolymerase-producing organisms were also evaluated (Liu et al., 2010). Bacterial isolates from the intestines of sturgeon, sea bass, and prawn were identified as Acidovorax spp. and Ochrobactrum spp. These organisms improved the survival of shrimp nauplii challenged with the pathogen V. campbellii (Liu et al., 2010). Taken
ACCEPTED MANUSCRIPT together, these studies indicate that such a strategy has the requisite potential to be applied on a large scale and reduce economic losses in the aquaculture industry. A search for bacteria that can inhibit the QS-mediated virulence of the fish pathogens Flavobacterium psychrophilum, Vibrio anguillarum, and A. hydrophila revealed that Pseudomonas sp. strain FF16 and Raoultella planticola strain R5B1 were the most
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effective. Raoultella planticola strain R5B1 did not affect the growth of the pathogenic
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bacteria; however, strain FF16 caused growth inhibition of A. hydrophila and F.
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psychrophilum. Given that Pseudomonas sp. strain FF16 exhibited antagonistic properties, it was proposed to be a good probiotic candidate for use in the salmon farming industry (Fuente
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et al., 2015). Edwardsiellosis, caused by the Gram-negative Edwardsiella tarda, is responsible for high mortality in marine fishes. The small peptide 5906 (MLFAGFM), which
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acts as a LuxS inhibitor and is produced by Escherichia coli strain DH5α/p5906. The recombinant bacterial strain was introduced intraperitoneally into Japanese founder fish.
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After four hours of injection, a reduction of approximately 86% colony forming units
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(CFU)/mg was observed in E. tarda TX1 recovered from fish liver where infection had been induced. Similarly, administration of the mammalian expression plasmid pID5906 which
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was injected into the muscle to the fish reduced bacterial counts by approximately 92.5% after 7 days of post plasmid administration. The effectiveness of the E. coli strain
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DH5α/p5906 was also tested on other aquatic pathogens, including A. hydrophila AH1 and V. harveyi T4. A 68% and 77% reduction in the cell counts of T4 and AH1, respectively, was observed in fish after 12 hours of injection with DH5α/p5906 (Sun and Zhang, 2016). Bacterial biofilms and exudates produced by Pseudoalteromonas sp. AMGP1 were observed to cause high mortality in the larvae of the mussel Perna canaliculus. In contrast, exudates of biofilms formed by Bacillus sp. AMGB1 and Macrococcus sp. AMGM1 helped to significantly improve larval settlement by 60% (Ganesan et al., 2010).
ACCEPTED MANUSCRIPT Micro-algae such as Chlamydomonas reinhardtii, C. mutablis, Chlorella fusca, and C. vulgaris produce a range of secondary metabolites which are reported to be important sources of QSIs (Teplitski et al., 2004). The red alga Ahnfeltiopsis flabelliformis was reported to produce compounds with the ability to act as AHL antagonists (Kim et al., 2007). Similar QSI molecules have been detected in extracts obtained from the marine bacteria Bacillus,
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Halobacillus, Lyngbya majuscula, and Symploc ahydnoides (Dobretsov et al., 2010; Teasdale
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et al., 2009, 2010).
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Another set of bioactive molecules that can be exploited to prevent these pathogens from causing disease in fishes is the halogenated furanones produced by the marine alga Delisea
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pulchra (Janssens et al., 2008). These molecules interact with LuxR-type receptors, resulting in reduced interactions with AHLs, consequently inhibiting gene expression. Additionally,
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these molecules block multichannel QSS in Vibrios (Table 1) (Defoirdt et al., 2007b). In aquatic habitats, marine micro-algae have been reported to produce halogenated
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compounds that interfere with communication among competing species. These compounds
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act through hydrogen peroxide-dependent inactivation of AHLs (Butler and Sandy, 2009; Defoirdt et al., 2013). This inactivation occurs through the haloperoxidase system of the
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diatom Nitzschia cf pellucida, which cleaves the acyl side chain of the signal molecules (Syrpas et al., 2014). Among marine organisms, the red alga D. pulchra, algae of the
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Caulerpaceae, Galaxauraceae, and Rhodomelaceae families, the red macroalga Asparagopsis taxiformis, micro-algae C. reinhardtii and Chlorella saccharophila, and the sponge Luffariella variabilis are reported to exhibit strong antagonistic behavior against QS (Table 1) (Syrpas et al., 2014). The fresh water alga C. saccharophila inhibited QS-mediated bioluminescence by inactivating AHLs (Table 1) (Natrah et al., 2011). Vibrio spp. belonging to the Harveyi clade are major pathogens affecting marine vertebrates and invertebrates. The role of indole in QS-mediated pathogenicity has been
ACCEPTED MANUSCRIPT reported (Lee et al., 2015; Mueller et al., 2009). Elevated levels of indole significantly affected QS-mediated exopolysaccharide production, motility, biofilm formation, and virulence by inhibiting the three-channel QSS of V. campbellii, a critical component responsible for virulence toward different aquatic hosts. Two analogs of indole, the auxin plant hormones, such as indole-3-acetic acid and indole-3-acetamide are reported to be
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produced by micro-algae (Yang et al., 2017). The survival rate of larvae was found to
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improve significantly when 50 and 100 µM concentrations of indole were added to brine
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shrimp rearing water. Given this information, larvae of a economically important aquaculture species, the giant river prawn (Macrobrachium rosenbergii), were exposed to indole. Here,
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the survival rate was significantly higher than that recorded for brine shrimp larvae. The basis for this higher survival was attributed to the effect of indole on QS-mediated virulence
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factors such as biofilm formation and exopolysaccharide production. Further evidence of the role of indole was gathered by observing its effect on QS-regulated bioluminescence. The
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inhibition of bioluminescence was caused by the blockage of the three-channel QSS by
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indole, which interfered with QS signal transduction. Such results have brought these
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applications of QSI closer to commercialization.
2.2 QSIs of plant origin
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Cinnamaldehyde isolated from cinnamon is a non-toxic flavoring agent that is generally regarded as safe. It has long been known for its antibacterial properties. However, it can act as a QSI in a manner similar to that observed in brominated thiophenones and furanones (Brackman et al., 2008). Addition of 10 mg/L pyrogallol protected the larvae of the brine shrimp A. franciscana and the giant river prawn M. rosenbergii. However, this QS disruption was shown to result mostly from the contribution of peroxide produced by this compound rather than direct QS inhibition (Table 1) (Defoirdt et al., 2013; Pande et al., 2013). In vitro
ACCEPTED MANUSCRIPT antibacterial activities of the essential oils of Hesperozygis ringens, Ocimum gratissimum, and O. americanum were quite effective against A. hydrophila infections in silver catfish (Rhamdia quelen). In treatments involving the use of 100–150 µg/mL of essential oils against A. hydrophila, hemolyisis of fish erythrocytes was reduced by 90–100%. Furthermore, their use to treat silver catfish infected with A. hydrophila resulted in 70–75% survival. Although
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the concentrations of these essential oils were 2–8-fold lower than their MIC values, their
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effect as QSIs was not demonstrated (Sutili et al., 2015).
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Curcumin, a natural plant phenolic product used as a QSI at a concentration of 25 μg/mL in rearing medium, reduced the bioluminescence of V. harveyi by 88%. It also significantly
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inhibited biofilm development and production of related virulence factors in different Vibrio spp., including V. harveyi, V. vulnificus, and V. parahaemolyticus. Treatment of A.
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franciscana nauplii with curcumin enhanced their survival rate by up to 67% against V. harveyi infection (Packiavathy et al., 2013). Curcumin along with lecithin and cholesterol
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was also used to prepare liposomes, which were tested for their ability to inhibit QS-
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mediated virulence factors such as swimming and swarming motility, biofilm formation, siderophore production, extracellular proteases, and AHL production at sub-MICs (Ding et
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al., 2017). Liposomes containing curcumin exhibited high encapsulation capacity (84.51%) and were stable and homogeneous. In silico studies revealed that curcumin released from the
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liposomes was found to interact with LuxI type protein, resulting in the blockage of AHL production in Aeromonas sobria, a pathogen known to affect many organisms including fish (Ding et al., 2017; Litwinowicz and Blaszkowska, 2014). An encouraging observation was reported from the use of coumarin, a chemical compound found at high concentrations in many plants such as bison grass, tonka bean, woodruff, cassia, cinnamon, and melilot (sweet clover). Coumarin was tested for its ability to inhibit QSmediated biofilm formation in E. coli, E. tarda, V. anguillarum, P. aeruginosa,
ACCEPTED MANUSCRIPT and Staphylococcus aureus. It also inhibited bioluminescence in Aliivibrio fischeri. These bacterial strains employ two different AIs, such as AHLs and AI-2 or AIP QSS. These results suggest that coumarin can act as a universal QSI to attenuate diseases caused by these pathogens in aquaculture. Coumarin was effective against a broad spectrum of pathogens as supported by its inhibitory action (at 100 and 125 μg) against pigment producing abilities of
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the three QS biosensor reporter strains (C. violaceum CV026, S. marcescens SP19 and A.
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tumefaciens NTL4) (Gutiérrez-Barranquero et al., 2015). At these concentrations, it also
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showed similar inhibitory effect against short, medium and long chain (C4HSL, C6HSL and 3OC8HSL of C. violaceum CV026, and S. marcescens SP19 and 3OC10HSL of A.
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tumefaciens NTL4. These inhibitory activities were linked to the suppression of promoter expression the pqsA and rhlI genes at 1.36 mM of coumarin, at different phases of bacterial
MA
growth. Since, the expression of the lasI promoter was not affected, the results indicated specificity in coumarin’s interaction with QSS, i.e., with the signal-receptor rather than the
D
production of the QS signal molecules. Since coumarin did not have any effect on cell
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attachment, it implied that formation of the mature biofilm was its target. A significant concentration-dependent effect of coumarin was also observed on the phenazine-producing
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ability of P. aeruginosa PA14 at 24 h. It also decreased the swarming motility of P. aeruginosa PA14 without effecting its swimming motility. The LuxI/R QS-mediated
AC
bioluminescence of A. fischeri, was also shown to be inhibited by coumarin at concentrations ranging from 1.0 to 2.0 mM. Further, coumarin also inhibited protease activity in Stenotrophomonas maltophilia and Burkholderia cepacia indicating species specificity. Since coumarin was also shown to inhibit the agr QS system-mediated biofilm formation in the Gram-positive pathogen S. aureus, it can be a potential universal QSI (GutiérrezBarranquero et al., 2015).
ACCEPTED MANUSCRIPT 2.3 Synthetic QSIs The major limitation in the use of natural QSIs is their production in very low concentration and their usage may prove toxic. In principle, QSIs can be synthesized chemically to overcome these limitations, however, such antagonists are still not produced commercially. A modification in the acyl chain of 3OC8-HSL involving the substitution of
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carbonyl at the 3-position with methylene was found to act as an antagonist of QS in
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Agrobacterium tumefaciens (Zhu et al., 1998). Pyrogallol and its analogs (aromatic diol-
SC
containing compounds and diols containing two five-membered rings) were reported to act at as antagonists against AI-2 mediated QS in V. harveyi at micromolar concentrations (Ni et
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al., 2008).
(5Z)-4-bromo-5-(bromomethylene)-3-butyl-2(5H)-furanone has been shown to act as
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antagonist of AHL and AI-2 QS signals in many organisms, although the half maximal inhibitory concentration (IC50) was in the high range of 25 to 100 µg/ml (Ren et al., 2004).
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The major limitation to the use of halogenated furanones is their toxicity. The application of
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synthetic QSIs such as brominated furanone [(Z-)-4-bromo-5-(bromomethylene)-2(5H)furanone] was reported to protect: (i) rainbow trout (Oncorhynchus mykiss) from infection
CE
caused by V. anguillarum at a low concentration of 2.5 μg/L (Rasch et al., 2004); (ii) shrimp (A. franciscana) from pathogenic strains of V. harveyi BB120 and V. campbellii at a
AC
concentration of 5 and 20 mg/L, respectively (Defoirdt et al., 2006); and (iii) giant freshwater prawn (M. rosenbergii) at 1 µM (Pande et al., 2013). As an alternative, sulfur-containing brominated thiophenones have been synthesized as sulfur analogs of brominated furanones, which can inhibit QSS by decreasing the DNAbinding potential of LuxRVh (Benneche et al., 2011; Defoirdt et al., 2007b). In contrast, the brominated thiophenone compound (Z)-4-{[5-(bromomethylene)-2-oxo2,5-dihydrothiophen-3-yl]methoxy}-4-oxobutanoic acid proved to be a highly promising
ACCEPTED MANUSCRIPT QSI, with an ability to completely protect gnotobiotic brine shrimp larvae and giant freshwater prawn from pathogenicity caused by V. harveyi BB120 at a concentration of 2.5 and 1.0 µM, respectively (Defoirdt et al., 2012; Pande et al., 2013). Thiophenones appear to be less toxic than furanones. From an application perspective, thiophenones were equally effective at 2.5 μM compared to furanones at 100 μM (Defoirdt et
PT
al., 2012). Most thiophenones inhibited bioluminescence in V. harveyi strains at 0.25 µM. A
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control strain showing QS-independent bioluminescence in the presence of the test
SC
compound was used to rule out false-positives. The compounds were also proficient enough to protect brine shrimp larvae from V. harveyi (Yang et al., 2015). Compounds such as
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thiazolidinediones, which structurally resemble N-acylaminofuranones and/or AHLs, and dioxazaborocanes that structurally resembled oxazaborolidine, were proposed to affect AI-2
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QS in V. harveyi, exhibiting half maximal effective concentration (EC50) values in very low concentration ranges of 2.1–61.2 µM. Their ability to inhibit bioluminescence in V. harveyi
D
QS mutants and at other DNA binding studies was found to result from the blockage of AI-2
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QS in V. harveyi by reducing the DNA-binding to the LuxR protein. Many dioxazaborocanes were found to target LuxPQ by blocking the AI-2 QSS (Brackman et al., 2013).
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AHL analogs having side chains longer than the native signal molecules are shown to be effective as QSIs (Hentzer and Givskov, 2003). AHL molecules (3OC6HSL and C6HSL)
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modified by acyl chain substitution at the C4-position inhibited bioluminescence in Vibrio fischeri (Reverchon et al., 2002). Similarly, analogs of AHLs with aryl substitutions were also found to act as antagonists (Lyon and Muir, 2003). Replacement of the carboxamide bond with a sulfonamide produced AHL analogs with an ability to inhibit bioluminescence activity of V. fischeri (Castang et al., 2004). AHL analogs - N-acyl cyclopentyl amines (CnCPAs) were effective as QSIs against P. aeruginosa (Ishida et al., 2007), Serratia marcescens (Morohoshi et al., 2007), and V. fischeri (Wang et al., 2008). Tetrahedral
ACCEPTED MANUSCRIPT geometrical changes in AHL due to sulfonamide or urea resulted in analogs which could inhibit QS-mediated functions of V. fischeri (Frezza et al., 2008). Two
semisynthetic
compounds
(7,8)
showed
excellent
QSI
activity
(anti-
bioluminescence) against marine bacteria associated with heavily fouled surfaces (Tello et al.,
2009).
Synthetic
QSIs
including
N-(propylsulfanylacetyl)-L-HSL,
N-
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(pentylsulfanylacetyl)-L-HSL, and N-(heptylsulfanylacetyl)-L-HSL were found to be
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effective as antipathogens at concentrations that did not have any evident effect on bacterial growth. They acted in vitro against the AHL synthase of A. salmonicida, leading to inhibition
SC
of virulence factors (Schwenteit et al., 2011). Synthetic analogs of γ-butyrolactone (honaucin
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A) containing a halogen atom at the 4-position of the crotonic acid subunit (4′bromohonaucin A and 4′-iodohonaucin A) were reported to be more potent inhibitors of QS
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in E. coli JB525 and V. harveyi BB120 than the naturally occurring honaucins (Choi et al. 2012).
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In marine systems, white band disease (WBD) is known to have devastating effects on the
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health of coral reefs, especially in Caribbean Acropora populations. The role of QS in causing the disease was demonstrated by the addition of signal molecules (AIs) to a healthy
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Acropora cervicornis microbiome (Certner and Vollmer, 2015). Use of the QSI (Z-)-4bromo-5-(bromomethylene)-2(5H)-furanone was found to be successful in the prevention of
AC
WBD. The most interesting and encouraging observation was that healthy microbes associated with the coral remained unaffected, as deduced from metagenomic studies (Certner and Vollmer, 2018).
2.4 Other strategies Plant extracts have been used to chemically synthesize anti-QS-nanoparticles for use in aquaculture as QSIs (Hamza et al., 2015; Mahanty et al., 2013). QS in Vibrio alginolyticus
ACCEPTED MANUSCRIPT can be attenuated by targeting the metabolic activity of serine/threonine kinase, which plays a crucial role between Type VI secretion systems and QS in this marine pathogenic organism (Yang et al., 2018).
3. Plant diseases
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Microbial-plant interactions result in a unique association wherein both partners generally
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benefit from the metabolic activities of one another. Microbes produce numerous bioactive
SC
molecules which have been shown to improve plant survival against bacterial and fungal attack (Arasu et al., 2015; Go et al., 2015; Jeyanthi and Velusamy, 2016; Shiva Krishna et
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al., 2015; Varsha et al., 2016). On the other end of the spectrum, this association may become pathogenic or parasitic, which is a major cause for concern. The infection of fruits,
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vegetables, and other crop plants with bacterial pathogens such as Pectobacterium, Agrobacterium, Pseudomonas, Burkholderia, Xanthomonas, and Xylella leads to heavy
D
economic losses (Mansfield et al. 2012). All of these organisms use QS to infect plants (Cho
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et al. 2007; Deng et al. 2011; Haudecoeur and Faure, 2010; Valente et al., 2017; von Bodman
CE
et al., 2003).
3.1 QSIs of microbial origin
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Vegetable plants such as potato, carrot, eggplant, celery, and Chinese cabbage are affected by soft-rot disease caused by bacterial pathogens such as Pectobacterium carotovorum, P. atrosepticum, and Dickeya spp. Pectobacterium carotovorum expresses its pathogenicity through the QSS. Cloning of the aiiA gene which codes for the AHL lactonase enzyme in P. carotovorum reduced disease symptoms (Dong et al., 2000). These AHL-lactonases were reported to be effective in protecting plants against Erwinia carotovora infections (Table 2) (Carlier et al., 2003; Mei et al., 2010; Riaz et al., 2008). Heterologous expression of aiiA
ACCEPTED MANUSCRIPT from Bacillus in Erwinia amylovora, the pathogen causing fire blight, effectively impaired the production of the extracellular polysaccharides amylovoran and levan, thereby reducing the symptoms of fire blight disease in apple (Molina et al., 2005; Zhao et al., 2008) (Table 2). The pathogenic behavior of Erwinia was restrained by expressing pro3A-aiiA in Bacillus thuringiensis (Zhu et al., 2006). The biocontrol agent Bacillus sp. A24 expressing the aiiA
PT
gene as well as Pseudomonas fluorescens containing the plasmid pME6863 to express aiiA
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reduced rot and gall symptoms caused by the phytopathogen P. carotovorum (Helman and
SC
Chernin, 2015). γ-caprolactones with lactonase-stimulating activity when supplemented in a microbial consortium showed an increased ratio of AHL-degrading bacteria and effectively
NU
inhibited soft rot disease caused by P. atrosepticum in potato crops (Table 2) (Cirou et al., 2011; Fetzner, 2015). Heterologous expression o gene aiiA from Bacillus spp. in non-
MA
pathogenic endophytic bacterium Burkholderia sp. KJ006 lowered AHL concentration to below threshold levels and consequently modified QS-mediated virulence. This genetically
D
modified bacterial strain showed a reduced incidence of seedling rot in rice plants (Cho et al.,
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2007).
Piericidin A and glucopiericidin A produced by Streptomyces xanthocidicus KPP01532
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effectively inhibited the pigment-producing ability of a C. violaceum sensor strain and QS activities regulating the expression of the virulence genes pelC, pehA, celV, and nip of E.
AC
carotovora subsp. atroseptica. Piericidin A at 50 µM and glucopiericidin A at 100 µM dramatically decreased the severity of rot in potato tubers caused by the pathogen E. carotovora (Table 2) (Kang et al., 2016). Another strategy for protecting plants from pathogens is the development of transgenic plants. Potato and tobacco plants transformed with the aiiA gene showed high resistance to P. carotovorum (Dong et al., 2001). These innovative methods have been highly effective in protecting plants from diseases. Economically important plants such as Amorphophallus
ACCEPTED MANUSCRIPT konjac and Chinese cabbage (Brassica rapa) that have been genetically modified with the aiiA gene prevented them from soft rot disease caused by P. carotovorum (Table 2) (Ban et al., 2009; Vanjildorj et al., 2009). Plant epiphytes harboring different species of Pseudomonas, Pantoea, and Erwinia were found to reduce the frequency of disease caused by Pseudomonas syringae. These bacteria
PT
produced the AHL signal in large quantities (up to 18-fold more than those produced by the
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pathogen), which negatively influenced the QSS of the pathogen. Premature induction of QS
SC
resulted in disease suppression on the leaf (Table 2) (Dulla and Lindow, 2009). The major QS factors that were negatively influenced included AhlR (a LuxR family protein), which
NU
helped to reduce disease lesions on the plant (Dulla et al., 2010). Here, siderophores quenched the iron available to the pathogenic bacteria, which in turn could not operate its
MA
QSS under iron-limiting conditions (Table 2) (Dulla et al., 2010; Karamanoli and Lindow, 2006).
D
Agrobacterium is a serious pathogen that causes crown gall tumors on plants of diverse
PT E
origins including plum, stone fruits, walnut, nut trees, cherry, sugar beets, grape vines, blackberry, rhubarb, and horseradish. To express its virulent behavior, Agrobacterium must
CE
possess a tumor-inducing plasmid (Ti plasmid, pTi). Agrobacterium tumefaciens regulates its QS-mediated gene expression through the signal molecule 3OC8HSL, which activates the
AC
transcription factor TraR. Agrobacterium tumefaciens also possesses an AHL lactonase encoded by attM which is quite different from that encoded by the aiiA of Bacillus but contains the conserved HXDH motif which is unique to this enzyme. AttM expression within the plant gall tumors appears to increase its fitness and enable inter-kingdom signaling. Production of Gamma-aminobutyric acid (GABA, a nonprotein amino acid) and salicylic acid in plants increases plant resistance to bacterial infection via attM expression (Table 2) (Chevrot et al., 2006; Haudecoeur et al., 2009; Yuan et al., 2007, 2008).
ACCEPTED MANUSCRIPT Rhizobium sp. strain NGR234 is unique because it carries multiple AHL-degrading genes: dhlR, qsdR1, qsdR2, aldR, and hydR-hitR (Krysciak et al., 2011). All AHL-lactonases can inactivate 3OC8HSL of P. aeruginosa and affect its motility, pyocyanin-producing ability, and biofilm-forming capacity. Heterologous expression of the AHL lactonases DlhR and QsdR1 in A. tumefaciens interfere with QS-regulated processes such as aberrant colonization
PT
of cowpea roots, thus aiding in plant growth (Krysciak et al., 2011).
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Xylella and Xanthomonas have been reported to be pathogenic to over 100 species belonging to both monocots and dicots of agricultural, ecological and ornamental plants. A
SC
few of the disease caused by Xylella fastidiosa and their hosts are as follows: Pierce’s disease
NU
of grapevine; Citrus Variegated Chlorosis, coffee leaf scorch, oleander leaf scorch; and olive quick decline syndrome; almond leaf scorch and diseases on other nut and shade tree crops
MA
(Rapicavoli et al., 2018). Similarly, different species of Xanthomonas cause the following diseases: (i) bacterial citrus canker, (ii) bacterial pustule of soybean; (iii) rice bacterial blight
D
disease, and (iv) black rot of crucifers (Deng et al., 2011). These pathogens cause diseases
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through diffusible signal factor (DSF)-mediated QSS (Deng et al., 2011). Signal molecules belonging to the DSF family are involved in QS regulation of virulence in several Gram-
CE
negative bacteria including Xanthomonas species as well as X. fastidiosa. However, numerous organisms belonging to the genera Bacillus, Pseudomonas, and Staphylococcus
AC
have been reported to rapidly degrade DSF signal molecules, thereby disrupting the DSFmediated virulence (Table 2) (Newman et al., 2008). carAB genes of Pseudomonas spp. which encode enzymes for the synthesis of carbamoylphosphate, a precursor molecule involved in the biosynthesis of pyrimidine and arginine were shown to be responsible for the rapid degradation of DSF (Newman et al., 2008). It was envisaged that overexpression of carAB genes could be a useful approach for biocontrol of plant pathogens that cause disease through the production of DSF. Transcriptomic analysis of QS mutants of rpfF, rpfC, and
ACCEPTED MANUSCRIPT rpfG genes, which are involved in the synthesis, perception, and transduction system responsible for DSF activity in Xanthomonas citri subsp. citri, revealed the diversity of their roles. Inhibition of DSF synthesis also reduces their attachment to leaves and decreases the symptoms of disease (Guo et al., 2012). Transgenic ‘Freedom’ grapes expressing exogeneous rpfF, which encodes the X.
PT
fastidiosa-derived enoyl-CoA hydratase that catalyzes the synthesis of DSF, had up to
RI
fourfold reduction in the incidence of disease, compared to parental line. This reduced
SC
incidence of infection was associated with restricted mobility of the pathogen in the genetically modified plant (Table 2) (Lindow et al., 2014). Subsequent studies showed that
NU
the transgenic plants Citrus sinensis and Carrizo citrange overexpressing rpfF of X. fastidiosa influenced the pathogenic symptoms caused by X. citri infection (Caserta et al., 2014). A
MA
variety of DSF species produced by the transgenic citrus plants were similar to those reported in rpfF-expressing grapes (Lindow et al., 2014), and were reported to affect QS signaling in
D
the pathogen (Caserta et al., 2014). This occurred because of the downregulation of DFS-
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responsive genes of X. citri, virulence genes, the type III secretion system, and endoglucanases by factors present in these transgenic plants (Caserta et al., 2014). A similar
CE
type of response involving reduction in the severity of disease caused by X. fastidiosa was also elicited by ectopic expression of rpfF in transgenic sweet orange and tobacco (Caserta et
AC
al., 2017). This decrease in disease severity was attributed to lower expression levels of the genes responsible for motility, leading to reduced microbial population sizes along the plant host.
3.2 QSIs of plant origin Curcumin, a phenolic compound extracted from turmeric, inhibited the biofilm-forming and virulence factor-producing abilities of P. aeruginosa in plant (Arabidopsis thaliana) and
ACCEPTED MANUSCRIPT animal (Caenorhabditis elegans) pathogenicity models (Table 2) (Rudrappa and Bais, 2008). Recent studies showed that phytochemicals including phenolic compounds such as carvacrol and eugenol (the major components of clove oil) reduced Pectobacterium aroidearum and P. carotovorum pathogenicity by reducing their biofilm-forming ability. These compounds acted by reducing the activities of the enzymes pectate, lyase, polygalacturonase, and
RI
PT
protease which are primarily responsible for plant cell-wall degradation (Joshi et al., 2016).
SC
3.3 Synthetic QSIs
Analogs of AHL with different geometric properties of C-S-C and C-C-C moieties
NU
affected signal-binding and consequently inhibited LuxR regulated-Green Fluoroscent Protein expression (Koch et al., 2005), LasR-mediated QS (Persson et al., 2005), and
MA
3OC6HS-mediated protease activity of Pectobacterium A2JM (Rasch et al., 2007). In silico searches for AHL analogs to compete for transcriptional regulators TraR (of A. tumefaciens)
D
and LasR (of P. aeruginosa) revealed that C7HSL, N-(4-bromophenylacetanoyl)-L-HSL, N-
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(2-cyclopentene-1-acetanoyl)-L-HSL,
N-(indole-3-butanoyl)-L-HSL,
and
N-(3-oxo-3-
phenylpropanoyl)-L-HSL competed for the positions otherwise taken by natural ligands
CE
(Ahumedo et al., 2010).
Rice grain rot disease is caused by Burkholderia glumae, which produces toxoflavin
AC
through C8HSL-mediated QS. (Chung et al., 2011). Compound J8-C8 targeted the TofI enzyme, whereas E9C-3oxoC6 acted by competitively inhibiting the binding of C8HSL to its receptor TofR (Table 2) (Chung et al., 2011). Synthetic compounds such as derivatives of N,N′-alkylated imidazolium functioned as QSIs against P. atrosepticum, reducing the disease symptoms of potato tubers (Des Essarts et al., 2013). Synthetic analogs of AHL (3OC6HSL) were demonstrated to be active in the wild type P. carotovora Ecc71 infecting their native host Solanum tuberosum (potato). Three AHL antagonists (OdDHL (8), p-bromo PHL (18)
ACCEPTED MANUSCRIPT and p-bromo phenylpropanoyl HL (22) were reported to be the most potent antagonists resulting in 72-84% inhibition in potato maceration. The study was extended to another host pathogen interaction: Phaseolus vulgaris (green bean) and P. syringae B278A, where these analogs were found to be equally effective. It shows that the AHL analogs have a broader
PT
host range (Palmer et al., 2011).
RI
3.4 Other strategies
SC
A glycoprotein (arginase) produced by sugarcane plants exhibits QSI properties, inhibiting the virulence caused by the fungal phytopathogen Sporisorium scitamineum. Interestingly,
NU
arginase acts as a false QS factor that induces agglutination of fungal teliospores, which confers the host plant with resistance to the pathogen (Sánchez-Elordi et al., 2015). Essential
MA
oils such as rosmarinic acid produced by plants may also mimic AHL signals by triggering a
4.1 Human pathogens
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4. Health care sector
D
self-defense mechanism (Corral-Lugo et al., 2016).
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Infectious diseases such as cystic fibrosis, bacterial endocarditis, chronic prostatitis, and oral cavities are at the core of virulent microbial behavior, which is mediated through QS.
AC
Scientific efforts are aimed at developing strategies for effectively disarming pathogens by employing QSIs.
4.1.1 QSIs of microbial origin Pseudomonas species are reported to possess QSIs such as AHL acylases (PvdQ, QuiP, HacB, and PA3922) (Huang et al., 2006; Sio et al., 2006; Wahjudi et al., 2011). The potential of these acylases to modulate the behavior and virulence of P. aeruginosa is quite variable.
ACCEPTED MANUSCRIPT Overexpressed PvdQ protein in its purified form attenuated the virulent behavior of Pseudomonas against nematodes (C. elegans) (Papaioannou et al., 2009). In contrast, overproduction of HacB did not significantly inhibit P. aeruginosa pathogenesis (Wahjudi et al., 2011). Recent studies have shown that lactonase (SsoPox-I) efficiently quenched QS in P. aeruginosa, thereby reducing the mortality of pneumonia in rats from 75% to 20% based
PT
on early treatment (Hraiech et al., 2014). Genetically engineered AHL lactonases could
RI
disrupt biofilm formation by the human pathogen A. baumannii (Chow et al., 2014).
SC
Maniwamycins isolated from ethyl acetate extracts obtained from Streptomyces sp. TOHO-MO25 and solonamides extracted from Photobacterium halotolerans S2753 inhibited
NU
the biosynthesis of pigments in C. violaceum CV026. These compounds exhibited antimicrobial effects only at high concentration of >1 mg/ml (Fukumoto et al., 2015;
MA
Machado et al., 2014). Solonamide B and its analogs, which act as structural mimics to antiinfectious prescriptions, were found to inhibit the agr QSS of S. aureus. These compounds,
D
however, do not exhibit any adverse reactions toward immune cell functions. The major
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limitation was the marginal effect of solonamides on fibronectin interaction and biofilm formation (Baldry et al., 2016). Apart from this approach, probiotic bacterial strains of
CE
Lactobacillus reutri have been shown to produce anti-agr compounds which can prevent exotoxin toxic shock syndrome toxin-1 production by pathogens (Li et al., 2011).
AC
Reduction in ulcers and abscesses caused by the S. aureus agrI strain was demonstrated by inhibiting agr activity in a mouse dermonecrosis model. Injection of high concentrations of AIP II peptide and hapten-linked AIP-4 into mice resulted in drastic reductions in pathogenicity caused by agr-strains (Park et al., 2007; Wright et al., 2005). Although many attempts have been made to develop synthetic anti-agr compounds to simultaneously target all types of AIPs, these agents are limited by their poor affinity (Lyon et al., 2000; Scott et
ACCEPTED MANUSCRIPT al., 2003; Wright et al., 2005). In contrast, interference with AgrC, which binds to AIP and is responsible for dimerization, was found to be more effective (Gray et al., 2013).
4.1.2 QSIs of plant origin Plants are well-known to produce a variety of secondary metabolites, including dietary
PT
phytochemicals such as ajoene, iberin, limonoids, furocoumarins, and others. These bioactive
RI
molecules are known to provide health benefits through their antimicrobial, antioxidant, pro-
SC
oxidant, and QSI activities, (Brackman et al., 2011, 2016; Kazemian et al., 2015; Ouyang et al., 2016; Sarkar et al., 2015).
NU
Combretum albiflorum was reported to produce flavanoids. Flavanoids such as flavonol, flavanone, flavone, and chalcone were found to reduce the amount of pyocyanin and elastase
MA
produced by P. aeruginosa but did not affect bacterial growth. The expression of several QSmediated genes in P. aeruginosa PAO1 was reduced by naringenin and taxifolin. The most
D
effective were those that reduced the production of AHL signals (Vandeputte et al., 2011).
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Leaves of Kalanchoe blossfeldiana were found to contain bioactive molecules with the potential to inhibit QS-mediated virulence factors in P. aeruoginosa (Sarkar et al., 2015).
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This process involved inhibition of AHL biosynthesis. Limonoids present in citrus fruits have a triterpenoid structure containing a furan ring. These limonoids, particularly isolimonic acid
AC
and ichangin, affected QS-based biofilm formation in V. harveyi by modulating the response regulator LuxO (Vikram et al., 2011). Quercetin, a flavanol found in various fruits and vegetables such as apples, grapes, onions, and tomatoes, exhibits potential as an anticancerous, antiapoptotic, and antioxidative agent. At a concentration of 16 µg/mL, it significantly reduced biofilm formation and reduced elastase, protease, and pyocyanin production in P. aeruginosa by 36–58%. Quercetin significantly reduced the expression of QS genes lasI, lasR, rhlI and rhlR by 34, 68, 57, and
ACCEPTED MANUSCRIPT 50%, respectively (Ouyang et al., 2016). Metabolites from various mushrooms are known for their medicinal importance and show promising QSI activities. Extracts from the fruiting bodies of Tremella fuciformis, a white jelly mushroom, exhibited QSI activity against C. violaceum strain CV026 without affecting its growth. The inhibition was attributed to competitive binding with AHL receptors (Zhu and Sun, 2008). Three strains of Phellinus
PT
igniarius (S3, S6, and H) showed high QSI activity when tested against C. violaceum CV026,
RI
but did not inhibit its growth (Zhu et al., 2012). Taken together, these observations suggest
SC
potential strategies for controlling detrimental infections caused by pathogens. Periodontitis, an inflammation of the tooth-supporting tissues, is caused by the Gram-
NU
negative bacterium Porphyromonas gingivalis. Epigallocatechin-3-gallate (EGCG), a major catechin in the green tea leaves of Camellia sinensis, is known for its antioxidant,
MA
anticancerous, and antimicrobial properties (Fournier-Larente et al., 2016; Yin et al., 2015). EGCG could inhibit quorum sensing mediated bioluminescence in V. harveyi BB170
D
(Fournier-Larente et al., 2016). Green tea extract at 50–125 µg/mL reduced the adherence of
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P. gingivalis by 27–91%, while EGCG reduced this value in the range of 19–62% at 25–62.5 µg/mL (Fournier-Larente et al., 2016). Green tea extract was also found to be effective
The
QSI characteristics
AC
2015).
CE
against P. aeruginosa, eliciting a 63.3% survival rate in infected C. elegans (Yin et al.,
of
dietary phytochemicals,
particularly at
sub-lethal
concentrations, were observed to inhibit violacein pigment production by the C. violaceum CV026 and CV 31532 system and swarming motility of P. aeruginosa PAO1 and E. coli O157:H7. These results provided a foundation for the development of new antipathogens to circumvent issues related to antimicrobial resistance (Vattem et al., 2007). Upon ingestion, certain fruits are metabolized by the gut microbiota to produce compounds such as urolithins. These compounds have the potential to improve intestinal health by inhibiting the QS-
ACCEPTED MANUSCRIPT mediated virulence of pathogens including Yersinia enterocolitica (Table 3) (Espín et al., 2013; Truchado et al., 2012). Members of the Combretaceae plant family have been traditionally used to treat bacterial infections. Leaf and bark extracts of C. albiflorum have been tested for their QSI activities against virulence factors of P. aeruginosa strain PAO1 and pigment production by C.
PT
violaceum CV026. Here, catechin was found to exhibit QSI activity and inhibit biofilm
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formation by P. aeruginosa with no growth-inhibitory effects. Catechin reduced the
SC
expression of lasI and lasR by 20–40% and rhlI and rhlR by 38–44% (Vandeputte et al., 2010). Two other members of this plant family, Conocarpus erectus and Bucida buceras, are
NU
known for their QSI activities (Adonizio et al., 2006). Acacia nilotica has been used as an ayurvedic medicine because of its antioxidant and QSI activities. The hydrolyzed ethyl
MA
acetate fraction and hydrolyzed crude extract of the green pod at 0.4% concentration exhibited QS inhibition of the C. violaceum wild-type strain ATCC 12472, reducing pigment
D
production by 60–80% (Singh (BN) et al., 2009). Traditionally, leaf extracts of the plant
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Terminalia catappa L. have been used for their antiseptic activity. The QSI activity of this leaf extract was detected through its ability to inhibit violacein pigment production in C.
CE
violaceum. A concentration of 62.5 μg/mL of the tannin-rich fragment of the extract caused a 50% reduction in the activity of the virulence determinant LasA of P. aeruginosa ATCC
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10145 and could completely inhibit the maturation of the biofilms of P. aeruginosa. This extract did not affect bacterial growth even at concentrations up to 962 μg/mL (Taganna et al., 2011). The pathogenicity of S. aureus is mediated by its agr and RAP/TRAP QSS. Hamamelitannin (2′,5-di-O-galloyl-d-hamamelose) found in the bark of witch hazel (Hamamelis virginiana) was reported to inhibit the RAP/TRAP QS of pathogens by blocking the TraP receptor. This increases the susceptibility of the S. aureus biofilm to antibiotics
ACCEPTED MANUSCRIPT (Brackman et al., 2016). Hydrastis canadensis, a perennial plant of the family Ranunculaceae, is a popular herbal medicine known for its anti-inflammatory and antimicrobial activities. It also produces bioactive compounds such as alkaloids (Scazzocchio et al., 2001). Extracts of this herb have been shown to inhibit the QS-Agr signaling system of S. aureus and inhibit α-toxin production (Cech et al., 2012). Malabaricone C derived from
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plants such as Myristica cinnamomea, Panax ginseng, Italian medicinal plants, orange, and
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broccoli has also been shown to act as a QSI (Chong et al., 2011; Koh et al., 2013).
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Syzygium aromaticum (clove) is a widely investigated spice used to treat dental caries and periodontal disease, asthma, and various allergic disorders. Extracts from the dried flower
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buds of S. aromaticum were shown to have QSI properties, as they inhibited pigment production of C. violaceum CV026 (the biosensor strain) and swarming motility in P.
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aeruginosa PAO1 (Husain et al., 2013; Krishnan et al., 2012). Clove bud oil inhibits QSmediated biofilm formation and disrupts the integrity of already-formed biofilms of P.
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aeruginosa. Clove oil at a concentration of 1% reduced biofilm formation by 85.3%, while
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increasing the dispersal of preformed biofilms by 50.4%. The treatment had no effect on the growth pattern of the pathogen. Decreases of 60%, 35%, and 24% were observed in
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swarming, swimming, and twitching motility, respectively. Exopolysaccharide and extracellular DNA release was also reduced by 91.9% and 65.5%, respectively. A 0.3-fold
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decrease in pqsA transcription was reported due to a decrease in kynurenine (61%), which is essential for the synthesis of the QS signal PQS. Porcine skin explants used to examine the ex vivo effects of 1% clove oil showed a significant decrease in bacterial load (Jayalekshmi et al., 2016). Syzygium cumini (Indian blackberry) is known for its anti-diabetic, antiinflammatory, and anti-bronchitis properties. The methanolic extract (1 mg/mL) of the fruit reduced the pigment-producing potential of C. violaceum by 82%, without effecting its growth. This fruit extract resulted in an 80% reduction in biofilm formation by the food-
ACCEPTED MANUSCRIPT borne pathogen, Klebsiella pneumoniae. The extract also increased bacterial sensitivity toward the antibiotic ofloxacine. Anthocyanin pigments were found to be the major components of the extract (Venkadesaperumal et al., 2016). QSI derivatives have reportedly been found in the extract of vanilla beans (Vanilla planifolia Andrews). A QSI that inhibited violacein production by C. violaceum CV026
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cultures has also been found in the extract (Choo et al., 2006). The effect of caffeine at 2.5
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mg/mL was initially found to efficiently retard the growth of bacteria such as E. coli,
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Enterobacter aerogenes, Proteus vulgaris, and P. aeruginosa (Dash and Gummadi, 2008; Norizan et al., 2013). Subsequently, caffeine was found to act as a QSI and a combination of
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caffeine and amoxicillin was reported to be effective against S. aureus (Esimone et al., 2008; Husain and Ahmad, 2015). The possibility of treating S. aureus infections with avellanin C
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produced by Hamigera ingelheimensis has been considered (Table 3) (Igarashi et al., 2015). Chinese herbs have long been used to treat various ailments such as pain, heart disease,
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fever, and fractures. Panax notoginseng and Prunella vulgaris exhibited QSI activity against
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P. aeruginosa PAO1 and C. violaceum CV026 using highly diluted herbal extracts (Koh and Tham, 2011). Another herb, Scutellaria baicalensis Georgi, also exhibited significant QSI
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activity. It did not exhibit growth inhibition when tested on P. carotovorum subsp. carotovorum and E. coli cells, therefore lacking antibacterial potential. QS inhibition
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potential was recorded in potato slices infected with P. carotovorum, which showed reduced soft rot symptoms (Song et al., 2012). Crude extracts of a traditional Chinese herb Phyllanthus amarus exhibited anti-QS activities against pigment production by C. violaceum CVO26, bioluminescence in E. coli sensor strains, and virulence gene expression of P. aeruginosa PAO1. In P. aeruginosa, the plant extracts reduced pyocyanin production, swarming motility, and lecA::lux expression. Inhibition of lecA expression was significant at a higher concentration of 3 mg/mL, whereas 1 mg/mL was sufficient to inhibit swarming
ACCEPTED MANUSCRIPT (Priya et al., 2013). Given these findings, Phyllanthus amarus may act as an important source of anti-pathogenic drugs. Essential oils contain a variety of volatile fatty acids which have antiseptic properties and thus are useful in food and medicine. Studies have reported the use of these compounds as QSIs. Essential oils extracted from Colombian plants showed QSI activities against AHL-
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based QS organisms, possessing the biosensor plasmids pKR-C12 (Pseudomonas putida) and
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pJBA132 (E. coli). Most essential oil components show QSI activity against short-chain
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AHLs. Extracts of Lippia alba showed approximately 65% and 18% inhibitory activity against pKR-C12 and pJBA132, respectively, whereas Ocotea spp. extracts showed 25% and
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71–76% inhibition at 1.25 mg/mL, respectively (Jaramillo-Colorado et al., 2012). Carvone was one of the major components of the essential oils exhibiting antimicrobial activities
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(Shahat et al., 2008). Essential oils from Colombian species of the Piper genus exhibit QSI activities against C. violaceum CV026 with no significant effect on growth. IC50 values of
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45.6, 93.1, and 513.8 μg/mL were found for Piper bredemeyeri, P. brachypodom, and P.
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bogotence, respectively (Olivero et al., 2011). Rosemary and tea tree essential oils at 0.5 and 0.25 µL/mL showed 50–80% inhibition of pigment production in C. violaceum ATCC
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12472. Extracts of propolis and bee pollen also showed QSI activity but required a higher MIC of 1.14 and 8.67 µL/mL, respectively. These compounds also showed significant
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antimicrobial activities against the food-borne pathogens E. coli O157:H7 and Listeria monocytogenes. These pathogens form biofilms on food-processing equipment and are responsible for food spoilage (Alvarez et al., 2012). Vegetables from the Brassicaceae family have gained interest because of the anticancer and
antibacterial
properties
of
their
secondary
metabolites.
These
metabolites
(glucosinolates) and their enzymatic hydrolysates, isothiocyanates (sulforaphane), also exhibit QSI properties against P. aeruginosa and E. coli sensor strains. Inhibition of the AHL
ACCEPTED MANUSCRIPT receptor LasR at a concentration of 50 µM was observed for sulforaphane. The compound was able to inhibit biofilm formation by P. aeruginosa strain PAO1 at a minimum concentration of 12 µM. More than 70% inhibition of pyocyanin production was also observed with 100 µM of sulforaphane and erucin (Table 3) (Ganin et al., 2013). Ajoene, a sulfur-containing compound extracted from garlic, was found to be a strong
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antipathogen. It attenuated QS-controlled virulence such as that of rhamnolipid, a heat-stable
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hemolysin. Along with tobramycin, in vitro biofilms were also greatly affected and P.
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aeruginosa infection was significantly cleared in a mouse model (Table 3) (Jakobsen et al., 2012a). Similarly, iberin from horseradish inhibited QS of the opportunistic pathogen P.
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aeruginosa (Jakobsen et al., 2012b).
A phenolic compound extracted from the cider of the apple Malus domestica showed
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strong antimicrobial activity against different pathogens such as Chronobacter sakazakii (Table 3) (Fratianni et al., 2012). The polyphenol compound pyrogallol present in tea can
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regulate QS-mediated bioluminescence in V. harveyi (Ni et al., 2008). Ginger, Zingiber
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officinale, has been traditionally used as an important food component. Phenolic compounds present in ginger, such as [6]-gingerol, [6]-shogaol, and zingerone exhibited strong QSI
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activities against pyocyanin and violacein production by P. aeruginosa and C. violaceum, respectively. An isoxazoline derivative of [6]-gingerol and [6]-azashogaol, a derivative of
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[6]-shogaol synthesized chemically, was also very effective against the QS activity of P. aeruginosa (Kumar et al., 2014). Vegetables in the Cruciferae family including broccoli produce isothiocyanates such as sulforaphane and erucin, which have strong QSI properties that can inhibit virulence caused by P. aeruginosa (Ganin et al., 2013). Diterpene phytols evaluated at sub-MICs reduced biofilm formation by P. aeruginosa PAO1 by 74–84%. This reduction was higher than those recorded for treatments with streptomycin and ampicillin. Phytol at an MIC of 0.5 effectively
ACCEPTED MANUSCRIPT reduced other QS-mediated activities such as twitching, flagella motility, and pyocyanin activity (Table 3) (Pejin et al., 2015).
4.1.3 QSIs of animal origin A few studies have reported QSI activity by compounds of animal origin. Meat extracts
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such as those from turkey and beef patties, chicken breast, and beef steak showed 84.4–
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99.8% AI-2 signaling inhibition (Lu et al., 2004). AI-2 signaling of reporter strain V. harveyi
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BB170 was found to be inhibited by compounds present in ground beef (Soni et al., 2008). Various fatty acids such as linoleic, oleic, stearic, and palmitic acids isolated from poultry
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meat extracts are reported to exhibit QSI effects (25–99%) on the V. harveyi BB170 sensor strain. These fatty acids were reported to inhibit AI-2 mediated signaling at linoleic acid
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concentrations from 0.1–10 mM, causing 99% inhibition at 10 mM (Widmer et al., 2007). Cattle milk has long been known to contain a variety of essential nutrients and antipathogens.
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Raw cow and she-camel milk were also reported to contain anti-QSIs when tested against C.
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violaceum CV026 (Abolghait et al., 2011). Colostrum hexasaccharide isolated from mare colostrum was shown to degrade AHL signals and could inhibit QS-regulated biofilm
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formation and the production of virulence factors by S. aureus. This compound at 5 mg/mL, when used synergistically with 15 µg/mL of antibiotics such as clindamycin, linezolid, and
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erythromycin, increased the susceptibility of methicillin-resistant S. aureus (Srivastava et al., 2015). Phenolic compounds present in honey are effective in inhibiting virulence and biofilm formation by the opportunistic pathogen P. aeruginosa. However, the major limitations of the use of these therapeutic polyphenols is their lower solubility in water and inadequate bioavailability. A unique drug delivery system fabricated using selenium nanoparticles and polyphenols of honey resulted in the enhancement of QSI activity against P.
ACCEPTED MANUSCRIPT aeruginosa PAO1, both in vitro and in vivo. Bioinformatic analysis revealed that QSI acted by binding to the QS receptor LasR (Prateeksha et al., 2017). QS inhibitory enzymes such as acylases and paraoxanases have been isolated from animals such as rats, mice, zebrafish, and even humans. Acylase I from porcine kidney has been used in aquaculture as well as in the health care sector to inhibit AHL-mediated biofilm
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formation by A. hydrophila and P. putida (Dong and Zhang, 2005; Paul et al., 2009).
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Paraoxanases from human epithelial cells as well as those extracted from the serum of
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mammals such as rats, goat, bovine, and horses inhibit AHL-mediated QS in P. aeruginosa (Stoltz et al., 2007; Yang et al., 2005). Crude extracts of the freshwater sponge
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Ochridaspongia rotunda showed strong inhibitory activities with respect to pyocyanin in the range of 42–49%, which was more effective than that recorded for ampicillin. The extract
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also affected twitching and flagella motility. Thus, this extract has the potential to produce bioactive compounds for controlling P. aeruginosa biofilm (Pejin et al., 2014).
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The process of wound healing is impeded by biofilm-forming bacteria. Antibacterial and
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antibiofilm therapies must be combined to inhibit this process and allow for rapid healing. Natural and synthetic cathelicidin peptides have been reported to have antimicrobial and
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antibiofilm activities against S. aureus. The peptide functions by preventing cell adhesion as an antibiofilm molecule at low concentrations. Their helical characteristics were instrumental
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in expressing these antipathogenic properties and can be exploited for treating chronic infections (Dean et al., 2011; Strempel et al., 2015). Peptide LL-37 produced in humans acts by modulating the innate immune response. Additionally, it also has weak antimicrobial activity and inhibits bacterial biofilm in vitro. This effect on biofilm was exerted by the ability of peptide LL-37 to reduce the attachment of bacterial cells and influence the QSS of P. aeruginosa (Overhage et al., 2008).
ACCEPTED MANUSCRIPT In addition to enzymes, novel natural compounds are being investigated for their QSI activities. One such compound is a human sex hormone, estrone, which was reported to compete with AHL signals for receptors and reduce Ti plasmid transfer by A. tumefaciens. When tested using reporter strains, the compound also showed QSI activity against P.
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aeruginosa (Beury-Cirou et al., 2013).
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4.1.4 Antibodies as QSIs
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Monoclonal antibodies (MAbs) for AHL inactivation and sequestration were developed using lactam-containing haptens. Here, the linkers acted as analogs of AHL acyl chains
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(Kaufmann et al., 2006). The MAb RS2-1G9, specific for 3OC12HSL, acted as a QSI against pyocyanin production in P. aeruginosa (Kaufmann et al., 2006). This antibody effectively
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protected murine macrophages from the cytotoxic effects of the QS signal 3OC12HSL, which induces apoptosis (Kaufmann et al., 2008). Immunization of mice with bovine serum
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albumin-conjugated 3OC12HSL enhanced the survival of the animal from P. aeruginosa
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infection (Miyairi et al., 2006). The unique feature of this study was its demonstration that the inhibition of QS did not affect the bacterial population in the lung (Miyairi et al., 2006).
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MAb XYD-11G2 was shown to hydrolyze 3OC12HSL and inhibit pyocyanin produced by P. aeruginosa (Marin et al., 2007). Transition state analogs of AHL, i.e., sulfones, mimic the
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native substrate, binding to the enzyme with even higher affinity compared to that of the native substrate, which enables them to act as AiiA enzyme inhibitors (Kapadnis et al., 2009). In Gram-positive bacteria, peptides act as QS signaling molecules; antibodies against these peptide signals have been designed. Hapten AP4-5 mimics the QS signal, specifically AIP-4, which is produced by S. aureus (Park et al., 2007). MAb AP4-24H11 was produced by BALB/c mice immunized with proteins carrying AP4-5. The MAb showed high
ACCEPTED MANUSCRIPT specificity and strong binding affinity for AIP-4 over other QS signal molecules. AP4-24H11 modulated the production of exoproteins, virulence factors, and biofilm formation (Park et al., 2007). When used as a pre-treatment, AP4-24H11 protected all mice from death, while the combination of S. aureus and AP4-24H11 prevented lesion formation in murine infections (Park et al., 2007). This immunization strategy appears to be a useful approach for
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developing QSIs.
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4.1.5 Synthetic QSIs
Efforts have also been made to develop synthetic compounds to inhibit QS in pathogenic
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bacteria in human care sector. Thiazolidinedione (TZD) and its derivatives showed QSI activity against V. harveyi and P. aeruginosa, anti-bacterial activity against Gram-positive
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Streptococcus pneumoniae, and inhibition of biofilm formation by Candida albicans. Application of 20 μM of a TZD derivative, TZD-C8 ((z)-5-octylidenethiazolidine-2, 4-
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dione), resulted in 70% biomass reduction in P. aeruginosa PAO1 biofilms with growth
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inhibition observed at a concentration of 20 mM. Inhibition of QS signal production and swarming motility was also observed in vitro. In silico docking predicted that TZD-C8 had
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very high affinity for LasI. Approximately 51 genes, including those of the pqsABCDE operon and lasI, were downregulated by this compound (Lidor et al., 2015).
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The QS signal molecule PQS is synthesized by P. aeruginosa by the condensation of anthranilate and β-keto-fatty acid. Analogs such as methyl anthranilate and halogenated anthranilate were reported to regulate the production of PQS and reduce virulent behavior (Calfee et al., 2001; Lesic et al., 2007). These compounds exhibited therapeutic properties, as they restricted the dissemination of the pathogen in a mouse model (Calfee et al., 2001; Coleman et al., 2008; Lesic et al., 2007). PQS production in P. aeruginosa can be inhibited by farnesol, a signal molecule produced by the fungal pathogen C. albicans. Additionally,
ACCEPTED MANUSCRIPT isoprenoids were found to act as effective QSIs (Cugini et al., 2007). It was shown that modifications in the AHL ring moiety can also produce effective antagonists. The cyclohexanone analog [N-(2-oxocyclohexyl)-3-oxododecanamide] of HSL (3OC12HSL) was effective as an antagonist of QS-mediated activities including biofilm formation by P. aeruginosa (Smith et al., 2003a). In the case of 3-oxo-C12-D10 (2-aminophenol), the
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aromatic ring was responsible for the QSI activity (Smith et al., 2003b).
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Nanoparticles are gaining importance as antipathogens. Incubation of silver nanoparticles
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(AgNPs) with biomass of the fungi Rhizopus arrhizus BRS-07 resulted in mycofabricated NPs (mfNPs). These mfNPs affected the transcription of lasI and lasR, which reduced AHL
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(C4HSL and C12HSL) production by 69–76%. The QSI did not affect growth but inhibited violacein pigment production by C. violaceum CV026 at 25 µg/mL and reduced virulence
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gene expression in the range of 15–96%. A higher concentration (50 µg/mL) of mfNPs was toxic to P. aeruginosa and human epithelial cells (Singh et al., 2015). A similar study
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reported the treatment of C. ablicans infection with essential oil-AgNPs (Szweda et al.,
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2015). To inhibit QS and virulence caused by the human pathogen S. aureus, a synthetic QSI in the form of a macrocyclic peptide was loaded into degradable polymer nanofibers. QSI-
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loaded nanofiber coatings were able to strongly inhibit agr-based QS in a reporter strain of S. aureus for at least two weeks (Kratochvil et al., 2017). Numerous other synthetic compounds
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that were found to be important for inhibiting pathogenesis through QS inhibition were: (i) metal oxide nanoparticle drugs, active against methicillin resistant S. aureus (MRSA) and E. coli (Agarwala et al., 2014); (ii) azithromycin, active against α-hemolysin and biofilm formation by S. aureus (Gui et al., 2014); (iii) aryl-l-cysteine sulphoxides and related organosulphur compounds, active against V. harveyi BB170 and V. harveyi BB152 (Kasper et al., 2014); and (iv) FS8 and tigecycline, which prevented biofilm formation by Staphylococcus strains (Simonetti et al., 2013).
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4.1.6 Field trials 4.1.6.1 Human health Laboratory-scale studies have shown that fimbrolides or furanones can act as QSIs by preventing microbial adhesion. These compounds were assessed for their safety in clinical
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experiments against various pathogens such as P. aeruginosa, S. marcescens, S. aureus, etc.,
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which infected the contact lenses of guinea pigs and human volunteers. The trial period of 30
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days for animals and 24 hours for humans demonstrated the effectiveness of fimbrolidecoated contact lenses against bacterial adherence. A 67–92% reduction in bacterial adherence
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was recorded, supporting their use as antipathogens (Zhu et al., 2008). A clinical trial employing QSIs as therapeutics for treating cystic fibrosis in human
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patients was reported by Prof. Givskov and his team (Smyth et al., 2010). This pilot-scale trial was conducted using 656 mg/day of garlic oil macerate. This concentration was much
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lower than the dose toxic to humans. Here, 26 patients were monitored for eight weeks. The
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results were promising in terms of improved lung function, bodyweight, and reduced disease symptoms. Though a few patients did show abnormal liver function, and some were
CE
adversely affected to a small extent, the study was groundbreaking and encouraged further trials (Smyth et al., 2010). A clinical trial of azithromycin, a macrolide with QSI properties,
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was performed on intubated patients to test for activity against P. aeruginosa infection. This QSI lead to a significant reduction in QS-mediated pathogenicity (van Delden et al., 2012). However, the study also cautioned that the inevitable evolution of organisms remains a problem, in that they may develop resistance to QSIs (Köhler et al., 2010). Another strategy under consideration is a combination of antibiotics and QSIs in different model systems. Galleria mellonella larvae and C. elegans infected with P. aeruginosa and a B. cepacia complex showed better survival following combined treatment. A tobramycin and
ACCEPTED MANUSCRIPT cinnamaldehyde combination reduced the bacterial load in the lungs of BALB/c mice infected with Burkholderia cenocepacia compared to the use of antibiotics alone (Brackman et al., 2011). These studies are among the few clinical trials using QSIs reported in the public domain (Reuter et al., 2016). A garlic-based oral care formulation with QS-inhibitory and anti-inflammatory properties has been patented and is in-use by dentists. A carbonate-based
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QSI formulation has also been patented by Colgate-Palmolive (New York City, NY, USA)
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for oral care to inhibit biofilm formation (Grandclément et al., 2016).
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A considerable amount of work in recent years has also focused on the development of stable and specific QSI enzymes through genetic manipulations for direct administration to
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patients (Koch et al., 2014; Luo et al., 2014). An AHL acylase inhalation system has been developed using AHL-acylase (PvdQ) in a direct inhaler to quench the virulence of P.
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aeruginosa in cystic fibrosis patients. The freeze-dried enzymes incorporated in trehalose and inulin showed high stability during four weeks of storage even at 55 °C (Wahjudi et al.,
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2013).
4.1.6.2 Water treatment
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Treating water to make it suitable for drinking uses the innovative technology of a Membrane Bioreactor (MBR) (Meng et al., 2017; Siddiqui et al., 2015). However, bacterial
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biofilm formation causes the membrane to lose permeability. Given that bacteria use their QSS for biofilm formation (Berlanga and Guerrero, 2016), this network was targeted to prevent membrane biofouling. Porcine kidney acylase was applied to the MBR. This treatment retarded the trans-membrane pressure, indicating a role for the enzyme in alleviating membrane biofouling within the MBR (Yeon et al., 2009a). The QSI enzyme acylase, when immobilized on nanofiltration membranes, was also shown to mitigate membrane biofouling. The enzyme remained stable and 90% of its activity was retained for
ACCEPTED MANUSCRIPT approximately 20 cycles and up to 38 hours of operation in a continuous crossflow nanofiltration system (Kim et al., 2011). Membrane fouling of a submerged MBR was inhibited by encapsulating the bacteria within a porous vessel. The QSI activity of the bacteria in the porous vessel was observed to be steady for more than 100 days of MBR operation. This success was attributed to the continuous regeneration of bacteria with QSI
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activity and demonstrated energy-saving efficiency by reducing the rate of aeration required
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to operate the MBR (Jahangir et al., 2012). To enhance the life of the enzymatic system, a
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magnetic enzyme carrier (MEC) was used to immobilize AHL-acylase. Continuous use of MEC with 29 cycles of reuse was demonstrated in this study in an operational MBR (Yeon et
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al., 2009b). In contrast to the AHL-acylase used by other researchers, an E. coli strain genetically modified using AHL-lactonase from Rhodococcus sp. was added to a microbial
days of operation (Oh et al., 2012).
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vessel carrying functional bacteria. The MBR was found to function successfully for over 80
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To study the anti-biofouling effectiveness of QSIs for municipal wastewater treatment
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plants, an encapsulated lactonase producing bacteria (Rhodococcus sp. BH4) was installed in scaled-up MBRs. Immobilized Rhodococcus sp. BH4 in alginate beads was incorporated in a
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semi-pilot-scale 35-L MBR using synthetic wastewater conditions. After continuous operation for 95 days, the hydraulic resistance observed in the QSI-MBR was lower than that
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observed after 10–14 days of conventional MBR operation. Entrapped cells improved the dewaterability of the sludge i.e., reduced both the capillary suction period and the resistance to caking (Maqbool et al., 2015). The antibiofouling potential of bacteria was evaluated in both a single stage round as well as a three-stage round of MBR testing at the pilot-study scale. In single-stage MBR biofouling measured as total membrane potential, build-up was reduced by nearly 500% when QSI beads were used. The total bound exopolysachharide was reduced by 15% and a 7-fold reduction in total attached biomass per unit area of
ACCEPTED MANUSCRIPT biomembrane was observed for the QSI-MBR. The aeration intensity demand was also reduced to one-third that of conventional reactors, resulting in an approximately 60% reduction in energy consumption. The beads were also found to be stable during the operation (Lee et al., 2016).
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4.2 Medical devices
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Hospital-acquired infections have been reported to occur frequently with the use of
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medical devices (Neoh et al., 2017). Furanone – 5-Fluorouracil (5-FU), a pyrimidine analog was reported to inhibit QS-mediated pathogenicity in P. aeruginosa (Ueda et al., 2009).
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Functionalized catheters coated with this compound proved effective during clinical trials (Jacobsen et al., 2008; Walz et al., 2010). In a clinical study based on 960 adult patients from
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intensive care units, it was observed that central venous catheters coated with QSI 5-FU were less likely to cause infection than those coated with chlorhexidine/silver sulfadiazine
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(Jacobsen et al., 2008; Walz et al., 2010). However, the correlation between QSI and the
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reduction in bacterial contamination was not clearly stated. Antibacterial efficacy of the QSI furanone and the biofilm inhibitor dihydropyrrol-2-one were tested against P. aeruginosa
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PAO1 and S. aureus SA38. Adhesions of S. aureus and P. aeruginosa on glass surfaces coated with these inhibitors were reported to decrease by 71% and 93%, respectively (Taunk
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et al., 2016). A unique strategy to combine the low-fouling characteristic of poly(ethylene glycol) (PEG) and the QSI properties of the synthetic compound 5-methylene-1-(prop-2enoyl)-4-(2-fluorophenyl)-dihydropyrrol-2-one (DHP) was employed to design a PEGDAP (1,3-diaminopropane)-DHP coating to prevent biofilm formation. Assays conducted using P. aeruginosa and S. aureus showed that PEGDAP-DHP in different ratios led to significant reduction in cell adhesion and biofilm formation (Ozcelik et al., 2017). Efforts to prevent catheter-associated urinary tract infections by C. albicans resulted in the development of a
ACCEPTED MANUSCRIPT delivery system for sustained release of QSI–TZD-8. In this system, varnishes could be retained on the catheters for eight days and they were effective in reducing biofilm formation (Shenderovich et al., 2015). The effects of norspermidine on biofilm formation and its eradication in the case of P. aeruginosa PAO1 warrant further commentary. A low dose of 0.1 mM initiated the inhibition
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of biofilm formation, whereas 1.0 mM was effective for eradicating a mature biofilm. Other
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advantages were a 45–69% decrease in QS-mediated pyocyanin, elastase, and protease
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activities (Qu et al., 2016). Studies of the biotechnological applications of these results provided useful insights; for instance, catheters immersed in this compound did not allow
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biofilm formation, preventing device–related infections (Qu et al., 2016). Polyhydroxyalkanoates (PHAs), commonly known as bioplastics, have been introduced as
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antibiofilm agents. Modifications of PHA resulted in the production of molecules with antibacterial and antiviral properties (Radivojevic et al., 2016). Modification of the
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monomeric composition of PHA involved regulating the feed-enabled synthesis of a polymer
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composed of monomers of (R)-3-hydroxyoctanoic acid, which was then modified to produce a library of compounds. Of these compounds, (E)-oct-2-enoic and (R)-3-hydroxyoctanoic
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acids were able to inhibit the QS-mediated pyocyanin production in P. aeruginosa PAO1 (Radivojevic et al., 2016).
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Biofilm formation can be avoided by reducing bacterial adhesion on an implant (Gallo et al., 2014). Membranes of PHA-homopolymers and co-polymers such as poly(3hydroxybutyrate-3-hydroxyhaxanoate) have been used to prevent biofilm formation on wounds and implant surfaces. These sheets, when loaded with lysozyme at a rate of 16.1 µg per 9.5 mm3 discs, were effective in inhibiting biofilm formation (Kehail and Brighan, 2018). Coating of the implants with the PHA copolymer enhanced and stabilized drug release within a given time period (Rașoga et al., 2017; Rodríguez-Contreras et al., 2017).
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5. Challenges in implementing QSI 5.1 The rise and fall of antibiotics The discovery of antibiotics was a boon for patients suffering from fatal diseases (Kalia et al., 2007). However, a strong selective pressure generated by the indiscriminate use of
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antibiotics to treat diseases has led to the emergence of drug-resistant bacterial strains (Ciofu
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et al., 1994). Many new antibiotics were developed to counter bacterial resistance but none of
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these lasted more than ten years. These repeated failures caused reluctance on the part of pharmaceutical companies to invest time and money in developing novel antibiotics (Kalia et
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al., 2007). It proved to be an opportunity for researchers to look for novel strategies to counter bacterial infections. The discovery of QSIs and their initial success has fueled efforts
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to improve their efficacy and diversify their applications. Unlike antibiotics, QSIs are unique in that they interfere with virulent gene expression in bacteria without affecting their growth.
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However, the apprehension already exists that these compounds may also generate selective
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pressure and provoke bacteria to develop resistance. At present, there is little evidence to support this concern; however, the possibility cannot be completely ruled out (Defoirdt et al.,
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2010b; Diggle et al., 2007; García-Contreras et al., 2013, 2016; Kalia et al., 2014; Koul et al.,
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2016; Maeda et al., 2012).
5.2 Emergence of resistance to QSIs Evidence supporting the possibility of the emergence of resistance to QSIs in bacteria has been generated by the use of QS-mutants. Mutants of P. aeruginosa showing greater efflux of QSI-brominated furanone (C30) were reported to be among the potential mechanisms to counter QS disruption (García-Contreras et al., 2015; Maeda et al., 2012). In fact, cystic fibrosis patients were reported to be infected by bacterial isolates carrying these efflux-
ACCEPTED MANUSCRIPT enhancing mutations and showed resistance to this QSI disruption (Maeda et al., 2012). This indicated that bacteria may be genetically equipped with arsenals able to counter QSIs. Under stress conditions, certain bacteria act as “social cheaters” in that they stop responding to the QSS, thereby affecting the efficacy of QSIs (Sandoz et al., 2007; Tay and Yew, 2013). However, since these mutants show reduced fitness, their chances of survival are expected to
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be low (Gerdt and Blackwell, 2014). Likelihood of the emergence of resistance to QSIs is
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also influenced by the mechanisms of action of the QSIs themselves.
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Presence of multiple QSS in certain microbes enhances the likelihood that heterodimers of transcriptional regulators will bind to promiscuous promoters, enabling bacteria to express
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genes to counter a wider range of environmental stresses, including those caused by QSIs (Decho et al., 2010; Koul and Kalia, 2017). The variability in the specific activities of AHL
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synthases in strains of E. carotovora and the multiplicity of LuxR signal receptor homologs in Burkholderia mallei are latent features which further support the bacterial potential to
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develop resistance to QSIs (Brader et al., 2005; Case et al., 2008). In P. aeruginosa, the QSS
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-rhl and -las are essential for biofilm formation and their disruption depends upon the antibiotics used and the host immune system (Bjarnsholt, 2005). The PQS system of P.
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aeruginosa acts to regulate programmed cell death, which induces the release of extracellular DNA. This unique system proves beneficial for the survival of the other members of the cell
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population (Hazan et al., 2016). The use of enzyme-based QSIs which act on QS signals outside the bacterial cell have been suggested to be ideal candidates (Defoirdt et al., 2010b; García-Contreras et al., 2013; Guendouze et al., 2017; Kalia and Purohit, 2011). The apprehension remains that bacteria may become provoked to produce larger quantities of QS signal molecules. In fact, it has been shown that QS-mediated swarming motility in Serratia liquefaciens and a LuxRregulated PluxI-gfp (ASV) fusion in a mouse model inhibited by QSI-brominated furanone
ACCEPTED MANUSCRIPT could be reversed by exogenous addition of AHLs (Givskov et al., 1996; Hentzer at al., 2003). Hence, we must ensure that enzymes with high hydrolytic activity and stability be employed. Although these hydrolytic enzymes have a very broad spectrum of activity, the chance exists for bacteria to react by modifying their QS signal molecules. Bacteria also have the potential to modify their LuxR receptors to improve affinity for QS signal molecules
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(Collins et al., 2005; Hawkins et al., 2007), requiring that the QSI enzymes be modified to
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detect AIs even at very low concentrations. Another challenge in treating these infectious
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bacteria is that their QS-mediated pathogenicity occurs at high cell density; therefore, the ability to detect these bacteria and their QS signals at low densities, i.e., before the onset of
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disease, is crucial.
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5.3 QSIs and the microbiome
A major shift in the microbial consortium present in the epibiotic microbiome was
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observed in healthy Caribbean corals as well as those affected by Black Band Disease
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(BBD). The dominant bacteria in the epibiomes were strains of Halomoas, Moritella, and Renibacterium, whereas the black band consortia were dominated by cyanobacterium
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Roseofilum and uncultured genera of Rhodobacteraceae and Bacteroidales, Desulfovibrio and Fusibacter, respectively. The QSI lyngbic acid was produced in the diseased state and
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acted as a natural antagonist of the QSS (CqsS/CAI-1) of Vibrio spp., which co-occur with Rosefilum reptotaenium within the BBD consortia (Meyer et al., 2016). Members of the microbial community present in the human body, such as Enterobacter sp. strain T1-1, have been reported to operate QS through AHLs (Yin et al. 2012a). The human gut microbiome is inhabited by strains of Klebsiella, Salmonella, Escherichia, and Enterobacter, which have a single LuxR homolog, SdiA, and do not possess acyl-HSL synthase, indicating that these organisms operate their QSS via eavesdropping on AHLs
ACCEPTED MANUSCRIPT produced by others such as Y. enterocolitica (Swearingen et al., 2013). In this scenario, QSIs can be expected to influence human health, including metabolic disorders, by affecting the gut microbiome (McCarthy and O’Gara, 2015; Hur and Lee, 2015). Dietary substances present in foods such as grapefruit, coffee, and garlic can thereby influence the QSS and
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possibly have medicinal impact (McCarthy and O’Gara, 2015).
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5.4 The ideal QSIs
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To prevent and minimize the evolution of QSI resistance, a few criteria have been established for their selection. QSIs should have: (i) low molecular weight; (ii) high
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specificity; (iii) no adverse effect on hosts; (iv) high stability; (v) resistance to degradation by host metabolism; and (vi) no negative influence on host microbiome (Hentzer and Givskov,
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2003; Rasmussen and Givskov, 2006; Rasmussen et al., 2005; Vattem et al., 2007). The efficacy of these QSIs must be demonstrated not only in sensor strains but also on clinical
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isolates. In addition, regulatory concerns must be addressed. The increasing range of QSIs is
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likely to aid in the development of innovative devices. The efficacy of QSIs against bacterial infections has been demonstrated largely using animal models; these studies are being
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extended to develop medical devices against bacterial infections in order to enlarge the scope of the therapeutic arsenal against pathogenic bacteria. QSIs can be expected to have
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numerous biotechnological applications in yet unexplored areas of economic importance (Bzdrenga et al., 2017).
6. Conclusion The field of QS-mediated infectious disease has been the focus of researchers worldwide. To counter the repeated failures of antibiotics against infectious diseases, efforts have shifted to using QSIs as antipathogens. Regulating bacterial infections in aquaculture by interfering
ACCEPTED MANUSCRIPT with QSS is an effective approach for reducing economic losses incurred in this industry. The potential of this therapy is promising since most of these compounds are produced naturally by organisms. Since the most widely reported QSS operate through AHLs, targeting them to inhibit bacterial pathogenesis becomes as obvious choice. Inactivation of AHLs released into the milieu has been realized to be better since it dioes not impose any selective pressure on
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the pathogen. Inactivation of AHLs through AHL lactonases and AHL-acylases has been
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widely reported (Kalia, 2013; Kalia and Purohit, 2011, Kumar et al., 2013). AHL-lactonases
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are preferred over AHL-acylases, as these are not limited by the acyl chain length and have a broad substrate range with specificity for (s)-configuration and long N-acyl substitutions
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(Fuqua et al., 2001; Liu et al., 2013; Thomas et al., 2005; Wang et al., 2004; Yin et al., 2012b). Here, the highest potential for application of AHL-lactonases as QSIs appears to lie
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in the use of Bacillus spp.: B. sonorensis, B. subtilis, and B. thuringiensis (Chu et al., 2014; Defoirdt et al., 2011b; Dong et al., 2000, 2001, 2002, 2004; Huma et al., 2011; Liu et al.,
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2013; Momb et al., 2008; Niu et al., 2014; Pan et al., 2008; Thomas et al., 2005; Yin et al.,
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2012b; Zhou et al., 2006; Zhu et al., 2006). AHL lactonase activities from a wide range of Bacillus spp. were reported to be in the range of: (i) 480-674 pmol/h/unit OD600 of the
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bacterial culture (Dong et al., 2002; Piper et al., 1993), and; (ii) 4.98-6.56 μg/h per 109 CFU/ml (Chan et al., 2010). Kinetic analysis of lactonases has revealed stronger catalytic
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efficiency for AHLs with: (i) completely reduced acyl chains, and (ii) long acyl side chains (Liu et al., 2013, Momb et al., 2008, Wang et al., 2004). Expression of AHL lactonases in different bacterial and eukaryotic hosts (aquaculture animals, zebrafish and Artemia shrimp) has been effective in reducing diseases caused by different pathogens (A. hydrophila, E. carotovora, V. campbellii) (Chu et al., 2014; Defoirdt et al., 2011b; Niu et al., 2014; Chen et al., 2010; Dong et al., 2000; Molina et al., 2003; Pan et al., 2008; Ulrich, 2004; Zhou et al., 2006). Among plant sources of QSIs, coumarin shows great potential in that it can act against
ACCEPTED MANUSCRIPT diverse QS signal molecules. Other strategies likely to prove effective are mechanisms for enhancing host secretion systems such as stress hormones. Large-scale trials are needed before we can actualize the benefits of this approach. Rather than developing novel antibiotics, studies should be aimed at searching for novel bioactive molecules, nanoparticles, etc., that can act both as antimicrobials and
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antipathogens. Efforts are being made and the concept is gaining momentum, as is evident
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from the wide variety of research activities related to this topic, including antimicrobials
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(López et al., 2017; Sajid et al., 2015), natural products and bioactive molecules (Blunt et al., 2015; Ray and Kalia, 2017; Saini and Keum, 2017; Sharma and Jangid, 2015; Thakur et al.,
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2017), nanotechnology (Wadhwani et al., 2016), and microbial diversity (Pooja et al., 2015; Sharma and Lal, 2017).
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The large reservoir of basic studies on the potential applications of QSIs in protecting humans from infectious diseases has boosted the morale of the scientific community.
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However, the real test lies in large scale trials on the effects of QSIs on infectious diseases.
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So far, limited effort has been directed to the use of QSIs. For the time being, we may have to manage with the use of phytonutrients as rich dietary sources of QSIs, the use of bioactive
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compounds to cause pseudo-induction of QS and expose bacteria to the immune system, and the eradication of biofilms to render pathogens susceptible to low doses of antibiotics.
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Although QSIs are giving hope to human beings for getting protected from bacterial pathogens, however, we should not overlook the fact that QSIs are not acting in the interest of bacteria. As bacteria have the necessary genetic machinery to counter any environmental stress, they may thus evolve to counter this inteference with their metabolic activities.
Acknowledgements
ACCEPTED MANUSCRIPT This work was supported by Brain Pool grant (NRF-2018H1D3A2001746) by National Research Foundation of Korea (NRF) to work at Konkuk University. This research was supported by Basic Science Research Program (2017R1A2B3011676, 2017R1A4A1014806) and
by
the
Intelligent
Synthetic
Biology
Center
of
Global
Frontier
Project
(2013M3A6A8073184) through the National Research Foundation of Korea (NRF) funded
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by the Ministry of Science, ICT & Future Planning.
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Zhu, C., Yu, Z., Sun, M., 2006. Restraining Erwinia virulence by expression of N-acyl homoserine lactonase gene pro3A-aiiA in Bacillus thuringiensis subsp leesis. Biotechnol.
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Bioeng. 95, 526–532.
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Zhu, H., Kumar, A., Ozkan, J., Bandara, R., Ding, A., Perera, I., Steinberg, P., Kumar, N., Lao, W., Griesser, S.S., Britcher, L., Griesser, H.J., Willcox, M.D., 2008. Fimbrolide-
CE
coated antimicrobial lenses: their in vitro and in vivo effects. Optom Vis. Sci. 85, 292-300. Zhu, H., Sun, S.J., 2008. Inhibition of bacterial quorum sensing-regulated behaviours by
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Tremella fuciformis extract. Curr. Microbiol. 57, 418–422. Zhu, H., Liu, W., Wang, S.X., Tian, B.Z., Zhang, S.S., 2012. Evaluation of anti-quorumsensing activity of fermentation metabolites from different strains of a medicinal mushroom, Phellinus igniarius. Chemotherapy 58, 195-199. Zhu, J., Beaber, J.W., More, M.I., Fuqua, C., Eberhard, A., Winans, S.C., 1998. Analogs of the autoinducer 3-oxooctanoyl-homoserine lactone strongly inhibit activity of the TraR protein of Agrobacterium tumefaciens. J. Bacteriol. 180, 5398-5405.
ACCEPTED MANUSCRIPT
Figure Caption
Fig. 1. Application of quorum sensing (QS) inhibitors for protecting: (i) plants, (ii) animals,
AC
CE
PT E
D
MA
NU
SC
RI
PT
and (iii) human beings from diseases caused by pathogenic bacteria through QS system.
ACCEPTED MANUSCRIPT Table 1. Biotechnological applications of quorum sensing inhibitors in aquaculture
Quorum sensing
Source
Target
Mode of activity
Applications
References
Tetradecanoyl-L-
Fresh water algae
Aeromonas
Block quorum
Protection of burbot
Natrah et
Homoserine Lactone
- Chlorella
hydrophila and
sensing (QS)
(Lota lota) larvae
al., 2012
(C14-HSL) / (10 µM)
saccharophila and
A. salmonicida
signal molecule
from Aeromonas
inhibitors / (Effective
RI
PT
Conc.)
synthesis, receptor
reinhardtii
interaction
C. saccharophila
Vibrio harveyi,
/ (1 µg/L)
CCAP211/48
QS antagonist
infection
Protection of fresh
Natrah et
Chromobacteriu
water animals from
al., 2011
m violaceum
Vibrio infection
NU
Secondary metabolites
SC
Chlamydomonas
MA
CVO26,
Escherichia coli
Brachymonas
V. harveyi, V.
Degrades QS
Protection of
Dang et al.,
(PHB) / (25 mM, 10
dentrificans,
campbellii
signal molecule -
Artemia from
2009;
mg/L, NA)
Bacillus sp.,
LMG21363
AHL
pathogens
Defoirdt et
PT E
Polyhydroxybutyrates
D
JB523
al., 2007a;
AC
CE
Bacillus circulans
PHB Depolymerase /
Acidovorax spp.
(1.25 g/L)
Halet et al., 2007 V. harveyi
Degrades QS
Protection of
Liu et al.,
and
signal molecule -
Artemia from
2010
Ochrobactrum
AHL
pathogens
Inactivates QS
Digestive enzyme
Cao et al.,
signal molecule –
resistant and
2012
AHL
thermostable
spp. AHL lactonase / (100
Bacillus sp. strain
mg/L)
AI96
A. hydrophila
ACCEPTED MANUSCRIPT lactonase as fish feed to prevent infections AHL lactonase / (200
Bacillus sp. QSI-1
µg/L)
A. hydrophila
Inactivates QS
Probiotic to reduce
Chu et al.,
YJ-1
signal molecule –
pathogenicity in
2014
AHL
zebrafish (Danio
PT
rerio)
Labrenzia
C. violaceum
Inactivates QS
µM)
alexandrii
CV026
signal molecule –
Protection of fishes
RI
AHL lactonase / (0.5
Ghani et al., 2014
Aquculture
inhabiting
pathogens such
bacteria,
as: Aeromonas.
Flaviramulus
Edwardsiella,
ichthyoenteri
haloperoxidase / (2
(Laminaria
µM)
digitata)
Cinnamaldehyde /
Bark of cinnamon
(100 µM)
trees
signal molecule –
aquaculture
2015
Deactivate N-β-
Inactivation of QS
Syrpas et
CVO26, E. coli
ketoacylated
mediated virulence
al., 2014
JB523
HSLs (AHLs)
of pathogens
V. harveyi
Decreases DNA
Protection of
Brackman et
binding ability of
Artemia shrimp
al., 2008
Decreases DNA
Protection of larvae
Pande et al.,
binding affinity of
of Macrobrachium
2013
LuxR
rosenbergii, (Giant
C. violaceum
PT E
CE
Zhang et al.,
D
Brown algae
AHL
Bark of cinnamon
LuxR V. harveyi
AC
µM)
Use as a probiotic in
and Vibrio spp.
Vanadium
Cinnamaldehyde / (1
Inactivates QS
NU
Fish intestine
MA
AHL lactonase / (NA)
SC
AHL
trees
fresh water prawn) from infection and mortality Pyrogallol / (10 mg/L)
Emblica officinalis
V. harveyi
Disrupts QSS
Protection of brine
Defoirdt et
shrimp and giant
al., 2013
river prawn from
ACCEPTED MANUSCRIPT infection Curcumin / (100
Plant
Vibrio spp.
µg/ml)
Attenuates QS
Treatment of nauplii
Packiavathy
mediated
of A. franciscana
et al., 2013
virulence Coumarin/ (1.36 mM)
Plant
V. anguillarum,
Inhibit biofilm
Protection of
Gutiérrez-
E. tarda
formation,
salmonid fish
Barranquero
PT
production of
et al., 2015
phenazines,
Hesperozygis
A. hydrophila
µg/ml)
ringens, Ocimum
NU
gratissimum and O. americanum Synthetic
V. harveyi
MA
Brominated furanones
-
SC
Essential Oil / (100
Thiophenones / (0.25
PT E
Synthetic
Sutili et al.,
catfish (Rhamdia
2015
quelen)
Protection of brine
Defoirdt et
signal
shrimp A.
al., 2007b
transduction
franciscana from infections
Vibrionaceae and
Antagonistic to
Prevention of white
Certner and
Flavobacteriacea
AHL
band disease on
Vollmer,
coral reefs
2018
Antagonistic
Protection of brine
Yang et al.,
binding to LuxR
shrimp larvae
2015
-
Brackman et
e members V. harveyi
analogues of
AC
µM)
Synthetic
CE
Furanone / (50 µM)
Protection of silver
Interferes with QS
D
/ (50 mg/L)
RI
swarming motility
furanones
receptors
Thiazolidinediones/
Structurally
V. harveyi
Antagonistic
(12.2-100 µM)
resembled N-
binding to LuxR
acylaminofuranon
receptors
al., 2013
es AHL analogues / (NA)
Pseudomonas sp.
Fish pathogens:
Blocks AHL
Use as a probiotic
Fuente et
strain FF16
Flavobacterium
synthesis
candidate for the
al., 2015
and Raoultella
psychrophilum,
salmon farming
ACCEPTED MANUSCRIPT planticola strain
Vibrio
industry
R5B1
anguillarum, and A. hydrophila
A peptide 5906 / (NA)
Escherichia coli
Edwardsiella
Inhibits AI-2
Protection of fish
Sun and
strain
tarda
activity
from
Zhang, 2016
DH5α/p5906
PT
Bacillus sp.
Pseudoalteromon
Inhibits biofilm
Improvement of
Ganesan et
AMBG1 and
as sp. AMGP1
formation
larval settlement of
al., 2010
RI
Biofilm exudate / (NA)
Edwardsiellosis
AMGM1 Microbes from
Opportunistic
culture EC3 and EC5 /
Penaeus
pathogens
(1 mg/L)
vannamei shrimp
AC
MA
CE
PT E
D
gut
Degrades AHLs
NU
Enrichment bacterial
SC
Macrococcus sp.
mussel – Perna canaliculus Improvement of the
Tinh et al.,
survival of first-
2008
feeding turbot larvae (Scophthalmus maximus L.)
ACCEPTED MANUSCRIPT Table 2. Biotechnological applications of quorum sensing inhibitors against plant pathogens
Quorum sensing
Source
Target
Mode of
inhibitor
Applications
References
Prevention of
Dong et al., 2000,
activity Pseudomonas
Pectobacterium
Inactivates
(AHL) Lactonase
fluorescens
carotovorum
quorum
potato and
sensing (QS)
tobacco plants
2001
RI
PT
Acylhomoserine lactone
signal
SC
molecule – AHL
tumefaciens
6276
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Erwinia strain
Bacillus
Erwinia amylovora
AHL Lactonase
Bacillus cereus
CE
AC
AHL Lactonase
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D
AHL Lactonase
Agrobacterium
MA
AHL Lactonase
Reduction of
Carlier et al.,
signal
virulence in plant
2003
Inactivates QS
Reduction in fire
Molina et al.,
signal
blight disease of
2005
molecule –
apple
molecule – AHL
AHL Erwinia
Inactivates QS
-
Zhao et al., 2008
Inactivates QS
Prevention of
Ban et al., 2009
signal
Amorphophallus
molecule –
konjac from soft
AHL
rot disease
Inactivates QS
Prevention of
Vanjildorj et al.,
signal
Chinese cabbage
2009
signal molecule – AHL
Amorphophallus
P. carotovorum
konjac
AHL Lactonase
Inactivates QS
Bacillus
P. carotovorum
ACCEPTED MANUSCRIPT molecule –
(Brassica rapa)
AHL
from soft rot disease
Bacillus spp. and P. P. carotovorum
Inactivates QS
Prevention of rot
Helman and
fluorescens
signal
and gall
Chernin, 2015
molecule –
symptoms
AHL Bacillus
Burkholderia
Inactivates QS
Prevention of
thuringiensis
glumae
signal
disease - seedling
RI
AHL Lactonase
PT
AHL Lactonase
SC
molecule –
Cho et al., 2007
rot of rice
AHL
Clove oil
P. carotovorum
NU
Phenolic compounds:
and P. aroidearum
Reduction in
ExpI/ExpR
pathogenicity of
proteins
P. aroidearum
γ- caprolactones
Rhodococcus
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stimulating AHL
AC
glucopiericidin A
CE
Lactonase
Piericidin A and
N,N′-bisalkylated
D
MA
carvacrol and eugenol
Bind to
Streptomyces
and P. carotovorum
Pectobacterium
Inactivates QS
Protection from
atrosepticum
signal
soft rot of potato
Cirou et al., 2011
molecule – AHL Competes with
Protection from
xanthocidicus
AHL binding
soft rot of potato
KPP01532
site
Synthetic
Joshi et al., 2016
Erwinia carotovora
P. atrosepticum
imidazolium salts
Kang et al., 2016
Antagonistic
Inhibition of
Des Essarts et al.,
binding to
blackleg and soft-
2013
LuxR
rot diseases of
receptors
potato plants and tubers
Compound J8-C8
Synthetic
B. glumae
Competetively
Inhibition of
Chung et al.,
inhibits QS by
virulence and rice
2011
ACCEPTED MANUSCRIPT binding to TofI
grain rot by the pathogen
Curcuma longa
Competetively
Inhibition of
Chung et al.,
inhibits QS by
virulence and rice
2011
binding to
grain rot by the
TofR
pathogen
Pseudomonas
Downregulate
Inhibition of
Rudrappa and
aeruginosa PAO1
the production
virulence in plant
Bais, 2008
of AHLs
(Arabidopsis
Plant leaves
Pseudomonas
MA
Bacterial epiphytes
NU
SC
RI
Curcumin
B. glumae
PT
Compound E9C-3oxoC6 Synthetic
CE
PT E
D
syringae
Plants
(Caenorhabditis elegans) models
Premnature
Suppression of
Dulla and
induction of
swarming motility
Lindow, 2009
QS
and disease of the leaf
Suppresses
Reduction in
ahll. limiting
disease lesions
Dulla et al., 2010
of iron A. tumefaciens
amino acid) and salicylic acid
animal
the availability
AC
GABA (the nonprotein
P. syringae
thaliana) and
Degrades
Transgenic plants
Chevrot et al.,
AHLs
less sensitive to
2006; Yuan et al.,
A. tumefaciens
2007; 2008
infection Free L-proline
Synthetic
A. tumefaciens
Antagonizes
Transgenic plants
Haudecoeur et al.,
plant-GABA
less sensitive to
2009
defense
A. tumefaciens infection
Carbamoylphosphate
Pseudomonas spp.
Xanthomonas
Degrades
Reduction in
Newman et al.,
ACCEPTED MANUSCRIPT campestris
Xylella fastidiosa
Diffusible
disease severity in
signal factor
mustard and
(DSF)
cabbage leaves
Degrades DSF
Reduction in
2008
disease severity in grape stem X. fastidiosa
Restricts QS
Reduction in
Lindow et al.,
mediated
disease severity in
2014
mobility
grape and severity
PT
Freedom grape
Citrus plants
Xanthomonas citri
AC
CE
PT E
D
MA
NU
DSF
SC
RI
DSF
of Pierce’s disease
Restricts QS
Reduction in
Caserta et al.,
mediated
disease severity in
2014
mobility
Citrus sinensis and Carrizo citrange plants
ACCEPTED MANUSCRIPT Table 3. Biotechnological applications of quorum sensing inhibitors against human pathogens
Quorum
Source
Target
Mode of activity
Applications
Garlic (Allium
Pseudomonas
Down-regulate
sativum L)
aeruginosa
quorum sensing (QS) infections inhibiting
References
sensing
Iberin
Horseradish
P. aeruginosa
Broccoli
P. aeruginosa
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(Brassica
Ginger extracts
P. aeruginosa
CE
(Curcuma
AC
longa)
O-glycosylated
Orange extracts
flavanones
Polyphenols
Apple extracts
Jakobsen et al., 2012a
RI
formation
Antagonist LasIR and Treatment of
Antagonists LasR
D
extracts
Phenolics
and rhlAB)
MA
rusticana)
oleracea)
virulence and biofilm
RhlI/R
(Armoracia
Sulforaphane
genes (lasA, chiC,
NU
extracts
Treatment of
SC
Ajoene
PT
inhibitors
Jakobsen et al., 2012b
infections inhibiting virulence and biofilm formation Treatment of
Ganin et al., 2013
infections inhibiting virulence and biofilm formation
Down-regulates
Inhibition of
LasI by binding of
pyocyanin and other
long acyl chains of
virulence factors
the compounds to
production
Kumar et al., 2014
LasR Yersinia
Induce QS
Inhibition of
enterocolitica
regulatory genes,
swimming motility
yenR (regulation of
and biofilm
AHLs) and flhDC
maturation in the
(motility)
enteropathogen
Inhibits perception
Food preservation,
E. coli,
Truchado et al., 2012
Fratianni et al., 2012
ACCEPTED MANUSCRIPT (Malus
Cronobacter
of AHLs by LuxR
antibacterial drugs
domestica var.
sakazakii
type signal receptors
Metabolism of
Y.
Inhibits AHL
Improvement of
Espín et al., 2013;
Ellagitannins
enterocolitica
synthesis through
intestinal health
Truchado et al., 2012
from fruits by
YenI/ YenR
gut microbiota
inhibition
Essential oils
Candida
Propolis and
from Lavender,
albicans, C.
Ag-TiO2
Lemon, Tea
glabrata,
nanoparticles
tree, Basil,
C. krusei
-
NU
Geranium,
MA
Cinnamon and Clove
V. harveyi
Modulate response
Inhibition of biofilm
seeds (Citrus
BB120
regulator gene luxO,
formation
PT E
D
Sour orange
aurantium L.)
Fenugreek seeds
inhibiting AI-2 mediated QS Inhibition of
extract
PAO1,PAF79;
production
virulence factor
(Trigonella
Aeromonas
production in human
foenum-
hydrophila
as well as aquatic
graecum L.)
WAF38
pathogens
Malagasy plant
P. aeruginosa
Reduces signal
Reduction in
Vandeputte et al.,
(Combretum
PAO1
perception by RhlR
virulence and
2010, 2011
albiflorum) Chamaemelum nobile flower extract
•
Inhibits AHL
AC Flavanoids
Vikram et al., 2011
P. aeruginosa
CE
Caffeine
Szweda et al., 2015
infections
Thyme,
Limonoids
Treatment of fungal
RI
Essential oils,
SC
Urolithins
PT
Annurca)
C. nobile
Husain and Ahmad, 2015
biofilm formation P. aeruginosa
-
Antibacterial role in• fighting infections
Kazemian et al., 2015
ACCEPTED MANUSCRIPT Kalanchoe
Kalanchoe
leaves extract
blossfeldiana
P. aeruginosa
Interferes with AHL
Inhibition of
production
virulence by drug
•
Sarkar et al., 2015
resistance strains freshwater
P. aeruginosa
Inhibit biofilm
Treatment of
sponge
PAO1
formation,
infections through
Ochridaspongia
twitching, flagella
medical foods
rotunda
motility and
P. aeruginosa
Inhibit biofilm
vegetables
PAO1
formation,
SC
Green
(chlorophyll
twitching, flagella
component)
motility and
NU
Phytols
Treatment of
Pejin et al., 2015
RI
pyocyanin activity
Pejin et al., 2014
PT
Extract
infections through medical foods
pyocyanin activity
Hamigera
Staphylococcu
ingelheimensis
s aureus
Inhibits agr
MA
Avellanin C
NRRL 29060
signalling pathway
Treatment of
•
staphylococci infections
Jelly fungi
Chromobacter
Binds to the active
Food preservatives,•
(melanin,
(Auricularia
um violaceum
site of LuxR type
antimicrobial drug
melanoid,
auricula)
PT E
CE
Quercetin
D
Pigments
pheomelanin)
Edible lichen
C. albicans
AC
(Usnea
longissima)
Zhu et al., 2011
AHL receptors
Induces farnesol
Treatment of
production known to
candidiasis by
regulate QS
sensitizing the
mediated virulence
fungus to
and biofilm
fluconazole (FCZ),
formation
antifungal drug
Cyclic
Lactobacillus
S. aureus
Down-regulate
Treatment of
dipeptides
reuteri RC-14
MN8
RNAII and RNAIII
menstrual-
transcripts from agr
associated toxic
locus
shock syndrome
(vaginal isolate)
Igarashi et al., 2015
Singh et al., 2015
•
Li et al., 2011
ACCEPTED MANUSCRIPT Engineered
Sulfolobus
variant of
P. aeruginosa
•
Degrades lactone
Reduction in
solfataricus
ring of 3-oxo-C12
Pneumonia severity
hyper-
(extremophilic
AHLs with
caused by
thermostable
archaea)
improved catalytic
Pseudomonas
efficiency
infection
lactonase SsoP
Hraiech et al., 2014
Thermostable
Geobacillus
Acinetobacter
Degrades lactone
lactonase
kaustophilus
baumannii
ring of AHLs
Chow et al., 2014
RI
catalytic efficiency,
S. aureus
Degrades AHLs
CE
PT E
D
MA
hexasaccharide
NU
Colostrum
AC
Pathogen inhibition by increased
SC
HTA426
Colostrum
PT
ox
stability, and substrate range of enzyme Inhibition of virulence and biofilm formation by antibiotic resistant strains
•
Srivastava et al., 2015
ACCEPTED MANUSCRIPT Quorum Sensing Inhibitors as Antipathogens: Biotechnological Applications
Vipin Chandra Kaliaa*, Sanjay K. S. Patel a, Yun Chan Kang b, Jung-Kul Lee a*
Department of Chemical Engineering, Konkuk University, Seoul 05029, Republic of Korea
b
Department of Materials Science and Engineering, Korea University, Anam-Dong,
RI
PT
a
Corresponding author:
NU
*
SC
Seongbuk-Gu, Seoul 02841, Republic of Korea
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D
MA
E-mail: [email protected] (V.C. Kalia) or [email protected] (J-K. Lee)
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Highlights
Quorum sensing (QS) mediated pathogenicity in aquaculture, plants, and humans
AC
QS inhibitors (QSIs) as antipathogens Bioetchnological applications of QSIs Field trials of QSIs in treating plants, water and humans
Vipin Chandra Kalia, Sanjay K.S. Patel, Yun Chan Kang, JungKul Lee PII: DOI: Reference:
S0734-9750(18)30190-3 https://doi.org/10.1016/j.biotechadv.2018.11.006 JBA 7317
To appear in:
Biotechnology Advances
Received date: Revised date: Accepted date:
10 May 2018 19 October 2018 18 November 2018
Please cite this article as: Vipin Chandra Kalia, Sanjay K.S. Patel, Yun Chan Kang, JungKul Lee , Quorum sensing inhibitors as antipathogens: biotechnological applications. Jba (2018), https://doi.org/10.1016/j.biotechadv.2018.11.006
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Quorum Sensing Inhibitors as Antipathogens: Biotechnological Applications
Vipin Chandra Kaliaa*, Sanjay K. S. Patel a, Yun Chan Kang b, Jung-Kul Lee a*
Department of Chemical Engineering, Konkuk University, Seoul 05029, Republic of Korea
b
Department of Materials Science and Engineering, Korea University, Anam-Dong,
RI
PT
a
Corresponding authors:
NU
*
SC
Seongbuk-Gu, Seoul 02841, Republic of Korea
AC
CE
PT E
D
MA
E-mail: [email protected] (V.C. Kalia) or [email protected] (J-K. Lee)
ACCEPTED MANUSCRIPT
Abstract The mechanisms through which microbes communicate using signal molecules has inspired a great deal of research. Microbes use this exchange of information, known as quorum sensing (QS), to initiate and perpetuate infectious diseases in eukaryotic organisms, evading the
PT
eukaryotic defense system by multiplying and expressing their pathogenicity through QS
RI
regulation. The major issue to arise from such networks is increased bacterial resistance to
SC
antibiotics, resulting from QS-dependent mediation of the formation of biofilm, the induction of efflux pumps, and the production of antibiotics. QS inhibitors (QSIs) of diverse origins
NU
have been shown to act as potential antipathogens. In this review, we focus on the use of QSIs to counter diseases in humans as well as plants and animals of economic importance.
MA
We also discuss the challenges encountered in the potential applications of QSIs.
AC
CE
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pathogens, quorum sensing.
D
Keywords: antipathogens, aquaculture, biofilm, human health, infectious diseases, inhibitors,
ACCEPTED MANUSCRIPT
Abbreviations Acylhomoserine lactone
AI
Autoinducer
AIP
Autoinducing peptide
DSF
Diffusible signal factor
HSL
Homoserine lactone
MBR
Membrane bioreactor
MIC
Minimum inhibitory concentration
PHAs
Polyhydroxyalkanoates
PQS
Pseudomonas quinolone signal
QS
Quorum sensing
QSI
Quorum sensing inhibitor
QSS
Quorum sensing system
C4HSL
N-butanoyl-L-HSL
C6HSL
N-hexanoyl-L-HSL
C7HSL
N-heptanoyl-L-HSL
C8HSL
N-octanoyl-L-HSL
C12HSL
N-dodecanoyl-L-HSL
RI
N-(3-hydroxyhexanoyl)-L-HSL
3OC6HSL
N-(3-oxohexanoyl)-L-HSL
3OC8HSL
N-(3-oxooctanoyl)-L-HSL
3OC10HSL
N-(3-oxodecanoyl)-L-HSL
3OC12HSL
N-(3-oxododecanoyl)-L-HSL
SC
NU
MA
D
PT E
CE
AC
OHC6HSL
PT
AHL
ACCEPTED MANUSCRIPT
1. Introduction Bacteria can exist as free-living forms or in association with other living organisms. Such symbiotic relationships are beneficial. However, pathogenic associations involving bacteria and humans and economically important plants and animals are a major cause of concern for
PT
their tendency to impose heavy economic losses. In humans, pathogenic bacteria lead to
people
are
reported
to
die
annually
due
to
infectious
diseases
SC
million
RI
infectious diseases that result in high rates of morbidity and mortality. In fact, nearly 5.7
(http://www.who.int/en/news-room/fact-sheets/detail/the-top-10-causes-of-death). Given that
NU
65% to 80% of these infections are caused by biofilm-forming bacteria, biofilms have become an obvious drug target (Grandclément et al., 2016; Lebeaux et al., 2013; Lewis,
MA
2007). Biofilms are formed by bacteria via a cell density-dependent phenomenon known as quorum sensing (QS) (Miller and Bassler, 2001). Bacteria found in QS-mediated biofilms
D
have been reported to tolerate up to 1000 times higher concentrations of antibiotics in
PT E
comparison to their planktonic counterparts (Olsen, 2015). Antibiotic tolerance was shown to occur in Pseudomonas aeruginosa PAO1 through the induction of the QS regulator VqsM,
CE
which in turn mediates the expression of an antibiotic resistance regulator, nfxB. Here, expression of the mexC-mexD-oprJ operon enabled bacteria to tolerate kanamycin,
AC
tetracycline, and quinolones (Liang et al., 2014; Poole et al., 1996). Enhancement of biofilm formation and antibiotic tolerance in P. aeruginosa has been shown to result from the release of extracellular DNA, a consequence of programmed cell death mediated by the QSregulated excretion of 2-N-heptyl-4-hydroxyquinoline-N-oxide molecule. Therefore, the release of this molecule is beneficial to the surviving cell population (Hazan et al., 2016). Transcriptomic
studies
on
the
QS
transcription
regulator
MvfR
(PqsR)
in P.
aeruginosa PA14 have shown that the QS-mediated expression of the enzymes - peroxidases
ACCEPTED MANUSCRIPT shielded bacteria from β-lactam antibiotics and reactive oxygen species (H2O2) (Maura et al., 2016). In addition, it was reported that antibiotics such as levofloxacin or meropenem are responsible for the over-expression of efflux pumps, stimulating QS-mediated biofilm formation that enables Acinetobacter baumannii to tolerate higher concentrations of antibiotics (He et al., 2015). In view of the multi-dimensional role of QS in increasing
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antibiotic tolerance in bacteria, strategies are being developed to reduce bacterial
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pathogenicity using QS inhibitors (QSIs) (Defoirdt, 2018).
1.1 Quorum sensing
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Bacteria communicate with one another through the QS system (QSS) to perform certain societal functions collectively at high cell densities. These processes prove costly and
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ineffective when bacterial densities are low (Heilmann et al., 2015). A wide range of microbes use the QSS as a defense mechanism by producing antibiotics, undergoing
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sporulation, forming biofilms, and even expressing bioluminescence (Castang et al., 2004;
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Hammer and Bassler, 2003; Liu et al., 2015; Miller and Bassler, 2001). Environmental stimuli including the nutrient profiles of media (especially limitations in nitrogen and iron,
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and concentrations of phosphate, magnesium, and amino acids), pH, temperature, osmolarity, glucose and oxygen availability, and redox state have all been reported to influence the
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expression of QS-mediated and QS regulatory genes (Bazire et al., 2005; Bollinger et al., 2001; DeLisa et al., 2001; Duan and Surette, 2007; Frederix and Downie, 2011; Hasegawa et al., 2005; Kim et al., 2005; McGowan et al., 2005; Sonck et al., 2009; Surette and Bassler, 1999; Wagner et al., 2003; Yates et al., 2002). Certain bacteria exploit the QSS to produce an arsenal that attacks other organisms through heightened expression of virulence and pathogenicity factors. Expression of pathogenicity and virulence via the QSS broadly involves the following steps: (i) synthesis of QS signal molecules; (ii) release of signal
ACCEPTED MANUSCRIPT molecules into the milieu; (iii) sensing and binding of the signal molecules to the membrane receptors at high cell density, (iv) retrieval of the receptor-signal complex by the cell and its binding to the promoter region; and (v) transcription of genes responsible for pathogenicity (Fig. 1) (Deng et al., 2011; Durán et al., 2016; Jayaraman and Wood, 2008). QS operates through the synthesis of small molecules called autoinducers (AIs) (Papenfort
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and Bassler, 2016). Autoinducing peptides (AIPs) have been shown to regulate QS in Gram-
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positive bacteria, such as various species of Clostridium, Enterococcus, Bacillus,
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Streptococcus, Staphylococcus, and Listeria (Koul et al., 2016; Monnet et al., 2016). On the other hand, Gram-negative bacteria such as different species of Acidothiobacillus,
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Acinetobacter, Burkholderia, Escherichia, Pseudomonas, Vibrio, and Yersinia employ another group of AIs: the acylhomoserine lactones (AHLs) (Koul et al., 2016; Schuster et al.,
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2013). In addition to these two major groups of AIs, the use of a wide range of signaling molecules by bacteria have been reported, including the following: (i) fatty acids
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by Burkholderia spp., Ralstonia solanacearum, Xanthomonas spp., and Xylella spp. (Flavier
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et al., 1997; Zhou et al., 2017); (ii) ketones by Legionella spp. and Vibrio spp. (Tiaden and Hilbi, 2012); (iii) epinephrine, norepinephrine, and
AI-3 by enterohemorrhagic
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bacteria (Kendall and Sperandio, 2007); (iv) Pseudomonas quinolone signal (PQS) (quinolones and diketopiperazines) by P. aeruginosa (Heeb et al., 2011; Pesci et al., 1999);
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and (v) pheromones and short peptides by Bacilli and Gram-positive bacteria (Grossman, 1995; Ng and Bassler, 2009). Autoinducer-2 (AI-2), a furanosyl borate diester, has been reported to be employed by both Gram-positive and Gram-negative bacteria for regulating their QS activities (Chen et al., 2002). Evidence of the occurrence of QS in extremophiles has been rather scarce: (i) the hyperthermophile Thermotoga maritima uses peptide-based QS (Johnson et al., 2005); (ii) the QSS of archaea and Oceanithermus profundus of phylum Deinococcus-Thermus is regulated by AI-2 signals (Kaur et al., 2018; Sun et al., 2004); and
ACCEPTED MANUSCRIPT (iii) haloalkaliphiles such as Natronococcus occultus (Paggi et al., 2003) and Halomonas (Llamas et al., 2005; Tahrioui et al., 2011) use AHL-based QS. It has been observed that most bacteria conduct QS through a single signal synthase gene and its corresponding transcription regulator. However, the presence of multiple QSS has been recorded among Bacillus, Clostridium, Pseudomonas, Sinorhizobium, Streptococcus, and Vibrio spp. (Kalia et
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al., 2014; Koul et al., 2016; Lee and Zhang, 2015; Plener et al., 2015). These multiple
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systems work in either a hierarchical manner or as a network (Miller et al. 2002; Mok et al.
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2003; Yarwood and Schlievert, 2003).
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1.2 Quorum sensing inhibition
Bacteria that can recognize this QS communication have developed the capacity to
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interfere with it at different stages. A wide range of QSIs have been reported to act by different mechanisms: (i) inhibiting the synthesis of signal molecules; (ii) enzymatically
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degrading the signal molecules; (iii) competing with signal molecules for binding to receptor
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sites; (iv) interfering with the binding of signal molecules to gene promoters and inhibiting gene expression; and (v) scavenging of AIs by antibodies and macromolecules such as
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cyclodextrins (Kalia, 2013; Kalia and Purohit, 2011; Kato et al., 2006, 2007; Morohoshi et al., 2013; Park et al., 2007). Enzymes produced by a wide range of prokaryotes with an
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ability to degrade QS signal molecules (AHLs in particular) include lactonases, oxidoreductases, acylases, and phosphotriesterase-like lactonases, (Fetzner, 2015), whereas oxidoreductases target AI-2 (Dong et al., 2000; Weiland-Bräuer et al., 2016). A variety of small molecules including certain intermediates of the AHL biosynthesis route, noncognate AHLs, and dicyclic peptides have also been reported to act as QSIs (Bauer and Robinson, 2002; Givskov et al., 1996). A wide variety of plants are known to synthesize QSIs that either degrade QS signals or compete for signal receptors (Brackman et al., 2008; Ni et al.,
ACCEPTED MANUSCRIPT 2008; Teplitski et al., 2011; Vattem et al., 2007). Extracts from different parts of Emblica officinalis (medicinal plant), Medicago truncatula, Curcuma longa, cinnamon, grape fruit, and other edible plants and fruits have been reported to be effective against infections caused by plant pathogens (Brackman et al., 2008; Gao et al., 2003; Girennavar et al., 2008; Kalia, 2103; Mathesius et al., 2003; Ni et al., 2008; Niu and Gilberts, 2004; Niu et al., 2006;
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Rudrappa and Bais, 2008). Bioactive molecules produced naturally by marine organisms and
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fungi and chemically synthesized compounds and antibodies have also been reported to act
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as QSIs (Certner and Vollmer, 2018; Defoirdt et al., 2012; Delago et al., 2016; Ding et al., 2017; Grandclément et al., 2016; Helman and Chernin, 2015; Huma et al., 2011; Joshi et al.,
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2016; Kalia, 2013; Kalia and Purohit, 2011; Reuter et al., 2016; Yang et al., 2018). An interesting feature of QSIs is that they operate at lower than minimum inhibitory
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concentration (MIC). Thus, bacteria do not perceive threats to their survival and continue to grow without causing disease (Kalia, 2013; Kalia and Purohit, 2011). QS-mediated
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production of violacein dye by Chromobacterium violaceum CV026 was completely blocked
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by 10-3 M of synthetic QSI-furanone-{5-hydroxy-3-[(1R)-1-hydroxy-2,2-dimethylpropyl]-4methylfuran-2(5H)-one}. However, at a higher concentration (10-2 M), the QSI proved toxic
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and resulted in growth inhibition (Martinelli et al., 2004). Evidence in support of the bacterial potential to develop resistance against QSIs will be presented in a subsequent section.
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QSIs have been widely investigated and show great potential for biotechnological applications (Table 1). Most studies have been conducted on a small scale, largely using biosensor strains; strategies for commercial applications must also be developed. Here, we focus on the potential biotechnological applications of QSIs in aquaculture, plants, and health care by reviewing field studies carried out in these areas primarily over the last four to five years.
ACCEPTED MANUSCRIPT 2. Aquaculture The aquaculture industry is among the fastest growing sectors of food production worldwide. It is severely impacted by pathogens, which cause infectious diseases leading to huge economic losses. The most prevalent aquatic pathogens, which kill fish, prawns, shrimp, and mollusks, are Vibrio spp. and Aeromonas spp. (Baker-Austin and Oliver, 2018;
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Fuente et al., 2015; Niu et al., 2014; Zhao et al., 2015). These pathogens also damage host
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tissues in shrimp and fish by producing lytic enzymes such as hemolysins, proteases,
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chitinases and lipases, (Defoirdt et al., 2010a; Sun et al., 2007; Teo et al., 2003a,b). Bacteria attack these animals via QS-mediated pathogenicity (Defoirdt, 2013a; Defoirdt et al., 2011a;
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Garde et al., 2010; Vanmaele et al., 2015; Yildiz and Visick, 2009). Apart from antibiotics, numerous treatment strategies have been deemed useful in aquaculture, including probiotics,
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prebiotics, and immunostimulants (Ganguly et al., 2010). However, studies are required to discover and test QSIs which can help minimize economic losses on the commercial scale.
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QSIs administered to aquatic organisms as feed supplements are gaining interest to confer
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protection against pathogens (Defoirdt, 2013a,b; Kalia and Kumar, 2015).
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2.1 QSIs of microbial origin
QSSs operate through AHLs whose specificity depends upon the length of the acyl side
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chain. AHLs that differ even slightly from the cognate AHLs cannot function effectively and may even prove inhibitory (Fuqua et al., 2001). In Aeromonas species, short-chain AHLs are dominant in regulating QS. However, long-chain AHLs can reduce virulence factors in Aeromonas hydrophila and A. salmonicida. Interestingly, burbot (Lota lota) larvae can be spared from mortality caused by these organisms through QS regulation by long-chain AHLs such as N-tetradecanoyl-L-homoserine lactone (HSL) (Table 1) (Natrah et al., 2012). One of the most extensively studied mechanisms for degrading AHL signals and preventing QS-
ACCEPTED MANUSCRIPT mediated pathogenic diseases is the use of AHL lactonases and AHL acylases (Kalia, 2013; Kalia and Purohit, 2011). The lactonase enzymes act by opening the lactone ring, whereas acylases act by cleaving the side chain of the AHL molecule. AHL lactonases have been widely reported to occur in Bacillus species (Defoirdt et al., 2011b; Kumar et al., 2013; Zhou et al., 2016). However, few organisms have been reported to possess enzymes presenting
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both activities, such as Deinococcus radiodurans R1, Photorhabdus luminescens subsp.
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laumondii TTO1, and Hyphomonas neptunium ATCC 15444 (Kalia et al., 2011; Kalia,
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2014). Lactone degrading bacteria enriched from the gut microbiome of the Penaeus vannamei shrimp helped improve survival during the first feeding in larvae of the turbot, maximus L.
(Tinh
et
al.,
2008).
Labrenzia
alexandrii,
an
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Scophthalmus
alphaproteobacterium, could degrade the QS signal molecules C6HSL, 3OC6HSL and
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OHC6HSL via its lactonase activity. Labrenzia sp. BM1 can be applied as a biocontrol agent in aquaculture to protect fish from pathogens (Ghani et al., 2014). These studies support the
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possibility of using QSIs as non-antibiotic-based novel strategies to counteract the high
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mortality rates reported in commercial scale production of marine fish. Oral administration of purified lactonase obtained from Bacillus sp. to zebrafish
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significantly reduced infection caused by A. hydrophila. The lactonase enzyme was also found to be stable in the presence of digestive enzymes, thus providing an easy and efficient
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strategy for preventing infections in fishes (Table 1) (Cao et al., 2012; Chu et al., 2014). The use of Bacillus sp. was shown to be instrumental in enhancing the survival of gnotobiotic brine shrimp (Artemia) during Vibrio campbellii infection. Here, Bacillus acted by enhancing the innate immunity of the shrimp and reducing the activities of Vibrio (Niu et al., 2014). A fish intestine-inhabiting bacterium, Flaviramulus ichthyoenteri Th78T, was also reported to exhibit QSI activity, which can be attributed to the expression of AHL lactonase. This
ACCEPTED MANUSCRIPT bacterial species can be considered to have a probiotic potential because of its ability to survive in the intestine by utilizing various available nutrients (Zhang et al., 2015). Polymers of short-chain fatty acids such as β-hydroxybutyrate are produced by diverse bacteria under environmental stress conditions (Kumar et al., 2013; Singh (M) et al., 2009). Recent studies have reported the biocontrol properties of these biomolecules (Radivojevic et
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al., 2016; Ray and Kalia, 2017). The use of polyhydroxybutyrate (PHB) and its polymer is
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reported to be effective for controlling V. campbellii infections in Artemia franciscana at 100
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mM (Table 1) (Defoirdt et al., 2007a). PHB addition to Artemia culture water at 1000 mg/L provided complete protection against Vibrio infections (Defoirdt et al., 2007a). This PHB
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effect was attributed to its degradation products, such as fatty acids, which may have been generated in the gut of starving Artemia nauplii. At present, the use of this fatty acid and its
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polymer as a protective agent is not economical (Defoirdt et al., 2007a). Enrichment cultures from activated sludge were shown to contain PHB-accumulating (32% of cell dry weight)
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organisms, which were phylogenetically close to Brachymonas dentrificans. This study
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further supported the use of PHB for protecting Artemia nauplii from V. campbellii infections (Halet et al., 2007). The concept was further developed by enriching bacteria that degrade
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AHLs and produce PHB (Dang et al., 2009; Kumar et al., 2013). A positive correlation was established between the survival of Artemia during Vibrio harveyi infection and PHB-
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accumulating organisms identified as Bacillus sp., Bacillus circulans, and Vibrio sp. It was proposed that bacteria which can degrade AHL and produce PHB can be exploited for controlling bacterial infections (Dang et al., 2009). To support the role of PHB degradation products as biocontrol agents, PHB depolymerase-producing organisms were also evaluated (Liu et al., 2010). Bacterial isolates from the intestines of sturgeon, sea bass, and prawn were identified as Acidovorax spp. and Ochrobactrum spp. These organisms improved the survival of shrimp nauplii challenged with the pathogen V. campbellii (Liu et al., 2010). Taken
ACCEPTED MANUSCRIPT together, these studies indicate that such a strategy has the requisite potential to be applied on a large scale and reduce economic losses in the aquaculture industry. A search for bacteria that can inhibit the QS-mediated virulence of the fish pathogens Flavobacterium psychrophilum, Vibrio anguillarum, and A. hydrophila revealed that Pseudomonas sp. strain FF16 and Raoultella planticola strain R5B1 were the most
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effective. Raoultella planticola strain R5B1 did not affect the growth of the pathogenic
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bacteria; however, strain FF16 caused growth inhibition of A. hydrophila and F.
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psychrophilum. Given that Pseudomonas sp. strain FF16 exhibited antagonistic properties, it was proposed to be a good probiotic candidate for use in the salmon farming industry (Fuente
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et al., 2015). Edwardsiellosis, caused by the Gram-negative Edwardsiella tarda, is responsible for high mortality in marine fishes. The small peptide 5906 (MLFAGFM), which
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acts as a LuxS inhibitor and is produced by Escherichia coli strain DH5α/p5906. The recombinant bacterial strain was introduced intraperitoneally into Japanese founder fish.
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After four hours of injection, a reduction of approximately 86% colony forming units
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(CFU)/mg was observed in E. tarda TX1 recovered from fish liver where infection had been induced. Similarly, administration of the mammalian expression plasmid pID5906 which
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was injected into the muscle to the fish reduced bacterial counts by approximately 92.5% after 7 days of post plasmid administration. The effectiveness of the E. coli strain
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DH5α/p5906 was also tested on other aquatic pathogens, including A. hydrophila AH1 and V. harveyi T4. A 68% and 77% reduction in the cell counts of T4 and AH1, respectively, was observed in fish after 12 hours of injection with DH5α/p5906 (Sun and Zhang, 2016). Bacterial biofilms and exudates produced by Pseudoalteromonas sp. AMGP1 were observed to cause high mortality in the larvae of the mussel Perna canaliculus. In contrast, exudates of biofilms formed by Bacillus sp. AMGB1 and Macrococcus sp. AMGM1 helped to significantly improve larval settlement by 60% (Ganesan et al., 2010).
ACCEPTED MANUSCRIPT Micro-algae such as Chlamydomonas reinhardtii, C. mutablis, Chlorella fusca, and C. vulgaris produce a range of secondary metabolites which are reported to be important sources of QSIs (Teplitski et al., 2004). The red alga Ahnfeltiopsis flabelliformis was reported to produce compounds with the ability to act as AHL antagonists (Kim et al., 2007). Similar QSI molecules have been detected in extracts obtained from the marine bacteria Bacillus,
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Halobacillus, Lyngbya majuscula, and Symploc ahydnoides (Dobretsov et al., 2010; Teasdale
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et al., 2009, 2010).
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Another set of bioactive molecules that can be exploited to prevent these pathogens from causing disease in fishes is the halogenated furanones produced by the marine alga Delisea
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pulchra (Janssens et al., 2008). These molecules interact with LuxR-type receptors, resulting in reduced interactions with AHLs, consequently inhibiting gene expression. Additionally,
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these molecules block multichannel QSS in Vibrios (Table 1) (Defoirdt et al., 2007b). In aquatic habitats, marine micro-algae have been reported to produce halogenated
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compounds that interfere with communication among competing species. These compounds
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act through hydrogen peroxide-dependent inactivation of AHLs (Butler and Sandy, 2009; Defoirdt et al., 2013). This inactivation occurs through the haloperoxidase system of the
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diatom Nitzschia cf pellucida, which cleaves the acyl side chain of the signal molecules (Syrpas et al., 2014). Among marine organisms, the red alga D. pulchra, algae of the
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Caulerpaceae, Galaxauraceae, and Rhodomelaceae families, the red macroalga Asparagopsis taxiformis, micro-algae C. reinhardtii and Chlorella saccharophila, and the sponge Luffariella variabilis are reported to exhibit strong antagonistic behavior against QS (Table 1) (Syrpas et al., 2014). The fresh water alga C. saccharophila inhibited QS-mediated bioluminescence by inactivating AHLs (Table 1) (Natrah et al., 2011). Vibrio spp. belonging to the Harveyi clade are major pathogens affecting marine vertebrates and invertebrates. The role of indole in QS-mediated pathogenicity has been
ACCEPTED MANUSCRIPT reported (Lee et al., 2015; Mueller et al., 2009). Elevated levels of indole significantly affected QS-mediated exopolysaccharide production, motility, biofilm formation, and virulence by inhibiting the three-channel QSS of V. campbellii, a critical component responsible for virulence toward different aquatic hosts. Two analogs of indole, the auxin plant hormones, such as indole-3-acetic acid and indole-3-acetamide are reported to be
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produced by micro-algae (Yang et al., 2017). The survival rate of larvae was found to
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improve significantly when 50 and 100 µM concentrations of indole were added to brine
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shrimp rearing water. Given this information, larvae of a economically important aquaculture species, the giant river prawn (Macrobrachium rosenbergii), were exposed to indole. Here,
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the survival rate was significantly higher than that recorded for brine shrimp larvae. The basis for this higher survival was attributed to the effect of indole on QS-mediated virulence
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factors such as biofilm formation and exopolysaccharide production. Further evidence of the role of indole was gathered by observing its effect on QS-regulated bioluminescence. The
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inhibition of bioluminescence was caused by the blockage of the three-channel QSS by
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indole, which interfered with QS signal transduction. Such results have brought these
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applications of QSI closer to commercialization.
2.2 QSIs of plant origin
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Cinnamaldehyde isolated from cinnamon is a non-toxic flavoring agent that is generally regarded as safe. It has long been known for its antibacterial properties. However, it can act as a QSI in a manner similar to that observed in brominated thiophenones and furanones (Brackman et al., 2008). Addition of 10 mg/L pyrogallol protected the larvae of the brine shrimp A. franciscana and the giant river prawn M. rosenbergii. However, this QS disruption was shown to result mostly from the contribution of peroxide produced by this compound rather than direct QS inhibition (Table 1) (Defoirdt et al., 2013; Pande et al., 2013). In vitro
ACCEPTED MANUSCRIPT antibacterial activities of the essential oils of Hesperozygis ringens, Ocimum gratissimum, and O. americanum were quite effective against A. hydrophila infections in silver catfish (Rhamdia quelen). In treatments involving the use of 100–150 µg/mL of essential oils against A. hydrophila, hemolyisis of fish erythrocytes was reduced by 90–100%. Furthermore, their use to treat silver catfish infected with A. hydrophila resulted in 70–75% survival. Although
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the concentrations of these essential oils were 2–8-fold lower than their MIC values, their
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effect as QSIs was not demonstrated (Sutili et al., 2015).
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Curcumin, a natural plant phenolic product used as a QSI at a concentration of 25 μg/mL in rearing medium, reduced the bioluminescence of V. harveyi by 88%. It also significantly
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inhibited biofilm development and production of related virulence factors in different Vibrio spp., including V. harveyi, V. vulnificus, and V. parahaemolyticus. Treatment of A.
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franciscana nauplii with curcumin enhanced their survival rate by up to 67% against V. harveyi infection (Packiavathy et al., 2013). Curcumin along with lecithin and cholesterol
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was also used to prepare liposomes, which were tested for their ability to inhibit QS-
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mediated virulence factors such as swimming and swarming motility, biofilm formation, siderophore production, extracellular proteases, and AHL production at sub-MICs (Ding et
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al., 2017). Liposomes containing curcumin exhibited high encapsulation capacity (84.51%) and were stable and homogeneous. In silico studies revealed that curcumin released from the
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liposomes was found to interact with LuxI type protein, resulting in the blockage of AHL production in Aeromonas sobria, a pathogen known to affect many organisms including fish (Ding et al., 2017; Litwinowicz and Blaszkowska, 2014). An encouraging observation was reported from the use of coumarin, a chemical compound found at high concentrations in many plants such as bison grass, tonka bean, woodruff, cassia, cinnamon, and melilot (sweet clover). Coumarin was tested for its ability to inhibit QSmediated biofilm formation in E. coli, E. tarda, V. anguillarum, P. aeruginosa,
ACCEPTED MANUSCRIPT and Staphylococcus aureus. It also inhibited bioluminescence in Aliivibrio fischeri. These bacterial strains employ two different AIs, such as AHLs and AI-2 or AIP QSS. These results suggest that coumarin can act as a universal QSI to attenuate diseases caused by these pathogens in aquaculture. Coumarin was effective against a broad spectrum of pathogens as supported by its inhibitory action (at 100 and 125 μg) against pigment producing abilities of
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the three QS biosensor reporter strains (C. violaceum CV026, S. marcescens SP19 and A.
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tumefaciens NTL4) (Gutiérrez-Barranquero et al., 2015). At these concentrations, it also
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showed similar inhibitory effect against short, medium and long chain (C4HSL, C6HSL and 3OC8HSL of C. violaceum CV026, and S. marcescens SP19 and 3OC10HSL of A.
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tumefaciens NTL4. These inhibitory activities were linked to the suppression of promoter expression the pqsA and rhlI genes at 1.36 mM of coumarin, at different phases of bacterial
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growth. Since, the expression of the lasI promoter was not affected, the results indicated specificity in coumarin’s interaction with QSS, i.e., with the signal-receptor rather than the
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production of the QS signal molecules. Since coumarin did not have any effect on cell
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attachment, it implied that formation of the mature biofilm was its target. A significant concentration-dependent effect of coumarin was also observed on the phenazine-producing
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ability of P. aeruginosa PA14 at 24 h. It also decreased the swarming motility of P. aeruginosa PA14 without effecting its swimming motility. The LuxI/R QS-mediated
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bioluminescence of A. fischeri, was also shown to be inhibited by coumarin at concentrations ranging from 1.0 to 2.0 mM. Further, coumarin also inhibited protease activity in Stenotrophomonas maltophilia and Burkholderia cepacia indicating species specificity. Since coumarin was also shown to inhibit the agr QS system-mediated biofilm formation in the Gram-positive pathogen S. aureus, it can be a potential universal QSI (GutiérrezBarranquero et al., 2015).
ACCEPTED MANUSCRIPT 2.3 Synthetic QSIs The major limitation in the use of natural QSIs is their production in very low concentration and their usage may prove toxic. In principle, QSIs can be synthesized chemically to overcome these limitations, however, such antagonists are still not produced commercially. A modification in the acyl chain of 3OC8-HSL involving the substitution of
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carbonyl at the 3-position with methylene was found to act as an antagonist of QS in
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Agrobacterium tumefaciens (Zhu et al., 1998). Pyrogallol and its analogs (aromatic diol-
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containing compounds and diols containing two five-membered rings) were reported to act at as antagonists against AI-2 mediated QS in V. harveyi at micromolar concentrations (Ni et
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al., 2008).
(5Z)-4-bromo-5-(bromomethylene)-3-butyl-2(5H)-furanone has been shown to act as
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antagonist of AHL and AI-2 QS signals in many organisms, although the half maximal inhibitory concentration (IC50) was in the high range of 25 to 100 µg/ml (Ren et al., 2004).
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The major limitation to the use of halogenated furanones is their toxicity. The application of
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synthetic QSIs such as brominated furanone [(Z-)-4-bromo-5-(bromomethylene)-2(5H)furanone] was reported to protect: (i) rainbow trout (Oncorhynchus mykiss) from infection
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caused by V. anguillarum at a low concentration of 2.5 μg/L (Rasch et al., 2004); (ii) shrimp (A. franciscana) from pathogenic strains of V. harveyi BB120 and V. campbellii at a
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concentration of 5 and 20 mg/L, respectively (Defoirdt et al., 2006); and (iii) giant freshwater prawn (M. rosenbergii) at 1 µM (Pande et al., 2013). As an alternative, sulfur-containing brominated thiophenones have been synthesized as sulfur analogs of brominated furanones, which can inhibit QSS by decreasing the DNAbinding potential of LuxRVh (Benneche et al., 2011; Defoirdt et al., 2007b). In contrast, the brominated thiophenone compound (Z)-4-{[5-(bromomethylene)-2-oxo2,5-dihydrothiophen-3-yl]methoxy}-4-oxobutanoic acid proved to be a highly promising
ACCEPTED MANUSCRIPT QSI, with an ability to completely protect gnotobiotic brine shrimp larvae and giant freshwater prawn from pathogenicity caused by V. harveyi BB120 at a concentration of 2.5 and 1.0 µM, respectively (Defoirdt et al., 2012; Pande et al., 2013). Thiophenones appear to be less toxic than furanones. From an application perspective, thiophenones were equally effective at 2.5 μM compared to furanones at 100 μM (Defoirdt et
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al., 2012). Most thiophenones inhibited bioluminescence in V. harveyi strains at 0.25 µM. A
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control strain showing QS-independent bioluminescence in the presence of the test
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compound was used to rule out false-positives. The compounds were also proficient enough to protect brine shrimp larvae from V. harveyi (Yang et al., 2015). Compounds such as
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thiazolidinediones, which structurally resemble N-acylaminofuranones and/or AHLs, and dioxazaborocanes that structurally resembled oxazaborolidine, were proposed to affect AI-2
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QS in V. harveyi, exhibiting half maximal effective concentration (EC50) values in very low concentration ranges of 2.1–61.2 µM. Their ability to inhibit bioluminescence in V. harveyi
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QS mutants and at other DNA binding studies was found to result from the blockage of AI-2
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QS in V. harveyi by reducing the DNA-binding to the LuxR protein. Many dioxazaborocanes were found to target LuxPQ by blocking the AI-2 QSS (Brackman et al., 2013).
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AHL analogs having side chains longer than the native signal molecules are shown to be effective as QSIs (Hentzer and Givskov, 2003). AHL molecules (3OC6HSL and C6HSL)
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modified by acyl chain substitution at the C4-position inhibited bioluminescence in Vibrio fischeri (Reverchon et al., 2002). Similarly, analogs of AHLs with aryl substitutions were also found to act as antagonists (Lyon and Muir, 2003). Replacement of the carboxamide bond with a sulfonamide produced AHL analogs with an ability to inhibit bioluminescence activity of V. fischeri (Castang et al., 2004). AHL analogs - N-acyl cyclopentyl amines (CnCPAs) were effective as QSIs against P. aeruginosa (Ishida et al., 2007), Serratia marcescens (Morohoshi et al., 2007), and V. fischeri (Wang et al., 2008). Tetrahedral
ACCEPTED MANUSCRIPT geometrical changes in AHL due to sulfonamide or urea resulted in analogs which could inhibit QS-mediated functions of V. fischeri (Frezza et al., 2008). Two
semisynthetic
compounds
(7,8)
showed
excellent
QSI
activity
(anti-
bioluminescence) against marine bacteria associated with heavily fouled surfaces (Tello et al.,
2009).
Synthetic
QSIs
including
N-(propylsulfanylacetyl)-L-HSL,
N-
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(pentylsulfanylacetyl)-L-HSL, and N-(heptylsulfanylacetyl)-L-HSL were found to be
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effective as antipathogens at concentrations that did not have any evident effect on bacterial growth. They acted in vitro against the AHL synthase of A. salmonicida, leading to inhibition
SC
of virulence factors (Schwenteit et al., 2011). Synthetic analogs of γ-butyrolactone (honaucin
NU
A) containing a halogen atom at the 4-position of the crotonic acid subunit (4′bromohonaucin A and 4′-iodohonaucin A) were reported to be more potent inhibitors of QS
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in E. coli JB525 and V. harveyi BB120 than the naturally occurring honaucins (Choi et al. 2012).
D
In marine systems, white band disease (WBD) is known to have devastating effects on the
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health of coral reefs, especially in Caribbean Acropora populations. The role of QS in causing the disease was demonstrated by the addition of signal molecules (AIs) to a healthy
CE
Acropora cervicornis microbiome (Certner and Vollmer, 2015). Use of the QSI (Z-)-4bromo-5-(bromomethylene)-2(5H)-furanone was found to be successful in the prevention of
AC
WBD. The most interesting and encouraging observation was that healthy microbes associated with the coral remained unaffected, as deduced from metagenomic studies (Certner and Vollmer, 2018).
2.4 Other strategies Plant extracts have been used to chemically synthesize anti-QS-nanoparticles for use in aquaculture as QSIs (Hamza et al., 2015; Mahanty et al., 2013). QS in Vibrio alginolyticus
ACCEPTED MANUSCRIPT can be attenuated by targeting the metabolic activity of serine/threonine kinase, which plays a crucial role between Type VI secretion systems and QS in this marine pathogenic organism (Yang et al., 2018).
3. Plant diseases
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Microbial-plant interactions result in a unique association wherein both partners generally
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benefit from the metabolic activities of one another. Microbes produce numerous bioactive
SC
molecules which have been shown to improve plant survival against bacterial and fungal attack (Arasu et al., 2015; Go et al., 2015; Jeyanthi and Velusamy, 2016; Shiva Krishna et
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al., 2015; Varsha et al., 2016). On the other end of the spectrum, this association may become pathogenic or parasitic, which is a major cause for concern. The infection of fruits,
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vegetables, and other crop plants with bacterial pathogens such as Pectobacterium, Agrobacterium, Pseudomonas, Burkholderia, Xanthomonas, and Xylella leads to heavy
D
economic losses (Mansfield et al. 2012). All of these organisms use QS to infect plants (Cho
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et al. 2007; Deng et al. 2011; Haudecoeur and Faure, 2010; Valente et al., 2017; von Bodman
CE
et al., 2003).
3.1 QSIs of microbial origin
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Vegetable plants such as potato, carrot, eggplant, celery, and Chinese cabbage are affected by soft-rot disease caused by bacterial pathogens such as Pectobacterium carotovorum, P. atrosepticum, and Dickeya spp. Pectobacterium carotovorum expresses its pathogenicity through the QSS. Cloning of the aiiA gene which codes for the AHL lactonase enzyme in P. carotovorum reduced disease symptoms (Dong et al., 2000). These AHL-lactonases were reported to be effective in protecting plants against Erwinia carotovora infections (Table 2) (Carlier et al., 2003; Mei et al., 2010; Riaz et al., 2008). Heterologous expression of aiiA
ACCEPTED MANUSCRIPT from Bacillus in Erwinia amylovora, the pathogen causing fire blight, effectively impaired the production of the extracellular polysaccharides amylovoran and levan, thereby reducing the symptoms of fire blight disease in apple (Molina et al., 2005; Zhao et al., 2008) (Table 2). The pathogenic behavior of Erwinia was restrained by expressing pro3A-aiiA in Bacillus thuringiensis (Zhu et al., 2006). The biocontrol agent Bacillus sp. A24 expressing the aiiA
PT
gene as well as Pseudomonas fluorescens containing the plasmid pME6863 to express aiiA
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reduced rot and gall symptoms caused by the phytopathogen P. carotovorum (Helman and
SC
Chernin, 2015). γ-caprolactones with lactonase-stimulating activity when supplemented in a microbial consortium showed an increased ratio of AHL-degrading bacteria and effectively
NU
inhibited soft rot disease caused by P. atrosepticum in potato crops (Table 2) (Cirou et al., 2011; Fetzner, 2015). Heterologous expression o gene aiiA from Bacillus spp. in non-
MA
pathogenic endophytic bacterium Burkholderia sp. KJ006 lowered AHL concentration to below threshold levels and consequently modified QS-mediated virulence. This genetically
D
modified bacterial strain showed a reduced incidence of seedling rot in rice plants (Cho et al.,
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2007).
Piericidin A and glucopiericidin A produced by Streptomyces xanthocidicus KPP01532
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effectively inhibited the pigment-producing ability of a C. violaceum sensor strain and QS activities regulating the expression of the virulence genes pelC, pehA, celV, and nip of E.
AC
carotovora subsp. atroseptica. Piericidin A at 50 µM and glucopiericidin A at 100 µM dramatically decreased the severity of rot in potato tubers caused by the pathogen E. carotovora (Table 2) (Kang et al., 2016). Another strategy for protecting plants from pathogens is the development of transgenic plants. Potato and tobacco plants transformed with the aiiA gene showed high resistance to P. carotovorum (Dong et al., 2001). These innovative methods have been highly effective in protecting plants from diseases. Economically important plants such as Amorphophallus
ACCEPTED MANUSCRIPT konjac and Chinese cabbage (Brassica rapa) that have been genetically modified with the aiiA gene prevented them from soft rot disease caused by P. carotovorum (Table 2) (Ban et al., 2009; Vanjildorj et al., 2009). Plant epiphytes harboring different species of Pseudomonas, Pantoea, and Erwinia were found to reduce the frequency of disease caused by Pseudomonas syringae. These bacteria
PT
produced the AHL signal in large quantities (up to 18-fold more than those produced by the
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pathogen), which negatively influenced the QSS of the pathogen. Premature induction of QS
SC
resulted in disease suppression on the leaf (Table 2) (Dulla and Lindow, 2009). The major QS factors that were negatively influenced included AhlR (a LuxR family protein), which
NU
helped to reduce disease lesions on the plant (Dulla et al., 2010). Here, siderophores quenched the iron available to the pathogenic bacteria, which in turn could not operate its
MA
QSS under iron-limiting conditions (Table 2) (Dulla et al., 2010; Karamanoli and Lindow, 2006).
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Agrobacterium is a serious pathogen that causes crown gall tumors on plants of diverse
PT E
origins including plum, stone fruits, walnut, nut trees, cherry, sugar beets, grape vines, blackberry, rhubarb, and horseradish. To express its virulent behavior, Agrobacterium must
CE
possess a tumor-inducing plasmid (Ti plasmid, pTi). Agrobacterium tumefaciens regulates its QS-mediated gene expression through the signal molecule 3OC8HSL, which activates the
AC
transcription factor TraR. Agrobacterium tumefaciens also possesses an AHL lactonase encoded by attM which is quite different from that encoded by the aiiA of Bacillus but contains the conserved HXDH motif which is unique to this enzyme. AttM expression within the plant gall tumors appears to increase its fitness and enable inter-kingdom signaling. Production of Gamma-aminobutyric acid (GABA, a nonprotein amino acid) and salicylic acid in plants increases plant resistance to bacterial infection via attM expression (Table 2) (Chevrot et al., 2006; Haudecoeur et al., 2009; Yuan et al., 2007, 2008).
ACCEPTED MANUSCRIPT Rhizobium sp. strain NGR234 is unique because it carries multiple AHL-degrading genes: dhlR, qsdR1, qsdR2, aldR, and hydR-hitR (Krysciak et al., 2011). All AHL-lactonases can inactivate 3OC8HSL of P. aeruginosa and affect its motility, pyocyanin-producing ability, and biofilm-forming capacity. Heterologous expression of the AHL lactonases DlhR and QsdR1 in A. tumefaciens interfere with QS-regulated processes such as aberrant colonization
PT
of cowpea roots, thus aiding in plant growth (Krysciak et al., 2011).
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Xylella and Xanthomonas have been reported to be pathogenic to over 100 species belonging to both monocots and dicots of agricultural, ecological and ornamental plants. A
SC
few of the disease caused by Xylella fastidiosa and their hosts are as follows: Pierce’s disease
NU
of grapevine; Citrus Variegated Chlorosis, coffee leaf scorch, oleander leaf scorch; and olive quick decline syndrome; almond leaf scorch and diseases on other nut and shade tree crops
MA
(Rapicavoli et al., 2018). Similarly, different species of Xanthomonas cause the following diseases: (i) bacterial citrus canker, (ii) bacterial pustule of soybean; (iii) rice bacterial blight
D
disease, and (iv) black rot of crucifers (Deng et al., 2011). These pathogens cause diseases
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through diffusible signal factor (DSF)-mediated QSS (Deng et al., 2011). Signal molecules belonging to the DSF family are involved in QS regulation of virulence in several Gram-
CE
negative bacteria including Xanthomonas species as well as X. fastidiosa. However, numerous organisms belonging to the genera Bacillus, Pseudomonas, and Staphylococcus
AC
have been reported to rapidly degrade DSF signal molecules, thereby disrupting the DSFmediated virulence (Table 2) (Newman et al., 2008). carAB genes of Pseudomonas spp. which encode enzymes for the synthesis of carbamoylphosphate, a precursor molecule involved in the biosynthesis of pyrimidine and arginine were shown to be responsible for the rapid degradation of DSF (Newman et al., 2008). It was envisaged that overexpression of carAB genes could be a useful approach for biocontrol of plant pathogens that cause disease through the production of DSF. Transcriptomic analysis of QS mutants of rpfF, rpfC, and
ACCEPTED MANUSCRIPT rpfG genes, which are involved in the synthesis, perception, and transduction system responsible for DSF activity in Xanthomonas citri subsp. citri, revealed the diversity of their roles. Inhibition of DSF synthesis also reduces their attachment to leaves and decreases the symptoms of disease (Guo et al., 2012). Transgenic ‘Freedom’ grapes expressing exogeneous rpfF, which encodes the X.
PT
fastidiosa-derived enoyl-CoA hydratase that catalyzes the synthesis of DSF, had up to
RI
fourfold reduction in the incidence of disease, compared to parental line. This reduced
SC
incidence of infection was associated with restricted mobility of the pathogen in the genetically modified plant (Table 2) (Lindow et al., 2014). Subsequent studies showed that
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the transgenic plants Citrus sinensis and Carrizo citrange overexpressing rpfF of X. fastidiosa influenced the pathogenic symptoms caused by X. citri infection (Caserta et al., 2014). A
MA
variety of DSF species produced by the transgenic citrus plants were similar to those reported in rpfF-expressing grapes (Lindow et al., 2014), and were reported to affect QS signaling in
D
the pathogen (Caserta et al., 2014). This occurred because of the downregulation of DFS-
PT E
responsive genes of X. citri, virulence genes, the type III secretion system, and endoglucanases by factors present in these transgenic plants (Caserta et al., 2014). A similar
CE
type of response involving reduction in the severity of disease caused by X. fastidiosa was also elicited by ectopic expression of rpfF in transgenic sweet orange and tobacco (Caserta et
AC
al., 2017). This decrease in disease severity was attributed to lower expression levels of the genes responsible for motility, leading to reduced microbial population sizes along the plant host.
3.2 QSIs of plant origin Curcumin, a phenolic compound extracted from turmeric, inhibited the biofilm-forming and virulence factor-producing abilities of P. aeruginosa in plant (Arabidopsis thaliana) and
ACCEPTED MANUSCRIPT animal (Caenorhabditis elegans) pathogenicity models (Table 2) (Rudrappa and Bais, 2008). Recent studies showed that phytochemicals including phenolic compounds such as carvacrol and eugenol (the major components of clove oil) reduced Pectobacterium aroidearum and P. carotovorum pathogenicity by reducing their biofilm-forming ability. These compounds acted by reducing the activities of the enzymes pectate, lyase, polygalacturonase, and
RI
PT
protease which are primarily responsible for plant cell-wall degradation (Joshi et al., 2016).
SC
3.3 Synthetic QSIs
Analogs of AHL with different geometric properties of C-S-C and C-C-C moieties
NU
affected signal-binding and consequently inhibited LuxR regulated-Green Fluoroscent Protein expression (Koch et al., 2005), LasR-mediated QS (Persson et al., 2005), and
MA
3OC6HS-mediated protease activity of Pectobacterium A2JM (Rasch et al., 2007). In silico searches for AHL analogs to compete for transcriptional regulators TraR (of A. tumefaciens)
D
and LasR (of P. aeruginosa) revealed that C7HSL, N-(4-bromophenylacetanoyl)-L-HSL, N-
PT E
(2-cyclopentene-1-acetanoyl)-L-HSL,
N-(indole-3-butanoyl)-L-HSL,
and
N-(3-oxo-3-
phenylpropanoyl)-L-HSL competed for the positions otherwise taken by natural ligands
CE
(Ahumedo et al., 2010).
Rice grain rot disease is caused by Burkholderia glumae, which produces toxoflavin
AC
through C8HSL-mediated QS. (Chung et al., 2011). Compound J8-C8 targeted the TofI enzyme, whereas E9C-3oxoC6 acted by competitively inhibiting the binding of C8HSL to its receptor TofR (Table 2) (Chung et al., 2011). Synthetic compounds such as derivatives of N,N′-alkylated imidazolium functioned as QSIs against P. atrosepticum, reducing the disease symptoms of potato tubers (Des Essarts et al., 2013). Synthetic analogs of AHL (3OC6HSL) were demonstrated to be active in the wild type P. carotovora Ecc71 infecting their native host Solanum tuberosum (potato). Three AHL antagonists (OdDHL (8), p-bromo PHL (18)
ACCEPTED MANUSCRIPT and p-bromo phenylpropanoyl HL (22) were reported to be the most potent antagonists resulting in 72-84% inhibition in potato maceration. The study was extended to another host pathogen interaction: Phaseolus vulgaris (green bean) and P. syringae B278A, where these analogs were found to be equally effective. It shows that the AHL analogs have a broader
PT
host range (Palmer et al., 2011).
RI
3.4 Other strategies
SC
A glycoprotein (arginase) produced by sugarcane plants exhibits QSI properties, inhibiting the virulence caused by the fungal phytopathogen Sporisorium scitamineum. Interestingly,
NU
arginase acts as a false QS factor that induces agglutination of fungal teliospores, which confers the host plant with resistance to the pathogen (Sánchez-Elordi et al., 2015). Essential
MA
oils such as rosmarinic acid produced by plants may also mimic AHL signals by triggering a
4.1 Human pathogens
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4. Health care sector
D
self-defense mechanism (Corral-Lugo et al., 2016).
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Infectious diseases such as cystic fibrosis, bacterial endocarditis, chronic prostatitis, and oral cavities are at the core of virulent microbial behavior, which is mediated through QS.
AC
Scientific efforts are aimed at developing strategies for effectively disarming pathogens by employing QSIs.
4.1.1 QSIs of microbial origin Pseudomonas species are reported to possess QSIs such as AHL acylases (PvdQ, QuiP, HacB, and PA3922) (Huang et al., 2006; Sio et al., 2006; Wahjudi et al., 2011). The potential of these acylases to modulate the behavior and virulence of P. aeruginosa is quite variable.
ACCEPTED MANUSCRIPT Overexpressed PvdQ protein in its purified form attenuated the virulent behavior of Pseudomonas against nematodes (C. elegans) (Papaioannou et al., 2009). In contrast, overproduction of HacB did not significantly inhibit P. aeruginosa pathogenesis (Wahjudi et al., 2011). Recent studies have shown that lactonase (SsoPox-I) efficiently quenched QS in P. aeruginosa, thereby reducing the mortality of pneumonia in rats from 75% to 20% based
PT
on early treatment (Hraiech et al., 2014). Genetically engineered AHL lactonases could
RI
disrupt biofilm formation by the human pathogen A. baumannii (Chow et al., 2014).
SC
Maniwamycins isolated from ethyl acetate extracts obtained from Streptomyces sp. TOHO-MO25 and solonamides extracted from Photobacterium halotolerans S2753 inhibited
NU
the biosynthesis of pigments in C. violaceum CV026. These compounds exhibited antimicrobial effects only at high concentration of >1 mg/ml (Fukumoto et al., 2015;
MA
Machado et al., 2014). Solonamide B and its analogs, which act as structural mimics to antiinfectious prescriptions, were found to inhibit the agr QSS of S. aureus. These compounds,
D
however, do not exhibit any adverse reactions toward immune cell functions. The major
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limitation was the marginal effect of solonamides on fibronectin interaction and biofilm formation (Baldry et al., 2016). Apart from this approach, probiotic bacterial strains of
CE
Lactobacillus reutri have been shown to produce anti-agr compounds which can prevent exotoxin toxic shock syndrome toxin-1 production by pathogens (Li et al., 2011).
AC
Reduction in ulcers and abscesses caused by the S. aureus agrI strain was demonstrated by inhibiting agr activity in a mouse dermonecrosis model. Injection of high concentrations of AIP II peptide and hapten-linked AIP-4 into mice resulted in drastic reductions in pathogenicity caused by agr-strains (Park et al., 2007; Wright et al., 2005). Although many attempts have been made to develop synthetic anti-agr compounds to simultaneously target all types of AIPs, these agents are limited by their poor affinity (Lyon et al., 2000; Scott et
ACCEPTED MANUSCRIPT al., 2003; Wright et al., 2005). In contrast, interference with AgrC, which binds to AIP and is responsible for dimerization, was found to be more effective (Gray et al., 2013).
4.1.2 QSIs of plant origin Plants are well-known to produce a variety of secondary metabolites, including dietary
PT
phytochemicals such as ajoene, iberin, limonoids, furocoumarins, and others. These bioactive
RI
molecules are known to provide health benefits through their antimicrobial, antioxidant, pro-
SC
oxidant, and QSI activities, (Brackman et al., 2011, 2016; Kazemian et al., 2015; Ouyang et al., 2016; Sarkar et al., 2015).
NU
Combretum albiflorum was reported to produce flavanoids. Flavanoids such as flavonol, flavanone, flavone, and chalcone were found to reduce the amount of pyocyanin and elastase
MA
produced by P. aeruginosa but did not affect bacterial growth. The expression of several QSmediated genes in P. aeruginosa PAO1 was reduced by naringenin and taxifolin. The most
D
effective were those that reduced the production of AHL signals (Vandeputte et al., 2011).
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Leaves of Kalanchoe blossfeldiana were found to contain bioactive molecules with the potential to inhibit QS-mediated virulence factors in P. aeruoginosa (Sarkar et al., 2015).
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This process involved inhibition of AHL biosynthesis. Limonoids present in citrus fruits have a triterpenoid structure containing a furan ring. These limonoids, particularly isolimonic acid
AC
and ichangin, affected QS-based biofilm formation in V. harveyi by modulating the response regulator LuxO (Vikram et al., 2011). Quercetin, a flavanol found in various fruits and vegetables such as apples, grapes, onions, and tomatoes, exhibits potential as an anticancerous, antiapoptotic, and antioxidative agent. At a concentration of 16 µg/mL, it significantly reduced biofilm formation and reduced elastase, protease, and pyocyanin production in P. aeruginosa by 36–58%. Quercetin significantly reduced the expression of QS genes lasI, lasR, rhlI and rhlR by 34, 68, 57, and
ACCEPTED MANUSCRIPT 50%, respectively (Ouyang et al., 2016). Metabolites from various mushrooms are known for their medicinal importance and show promising QSI activities. Extracts from the fruiting bodies of Tremella fuciformis, a white jelly mushroom, exhibited QSI activity against C. violaceum strain CV026 without affecting its growth. The inhibition was attributed to competitive binding with AHL receptors (Zhu and Sun, 2008). Three strains of Phellinus
PT
igniarius (S3, S6, and H) showed high QSI activity when tested against C. violaceum CV026,
RI
but did not inhibit its growth (Zhu et al., 2012). Taken together, these observations suggest
SC
potential strategies for controlling detrimental infections caused by pathogens. Periodontitis, an inflammation of the tooth-supporting tissues, is caused by the Gram-
NU
negative bacterium Porphyromonas gingivalis. Epigallocatechin-3-gallate (EGCG), a major catechin in the green tea leaves of Camellia sinensis, is known for its antioxidant,
MA
anticancerous, and antimicrobial properties (Fournier-Larente et al., 2016; Yin et al., 2015). EGCG could inhibit quorum sensing mediated bioluminescence in V. harveyi BB170
D
(Fournier-Larente et al., 2016). Green tea extract at 50–125 µg/mL reduced the adherence of
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P. gingivalis by 27–91%, while EGCG reduced this value in the range of 19–62% at 25–62.5 µg/mL (Fournier-Larente et al., 2016). Green tea extract was also found to be effective
The
QSI characteristics
AC
2015).
CE
against P. aeruginosa, eliciting a 63.3% survival rate in infected C. elegans (Yin et al.,
of
dietary phytochemicals,
particularly at
sub-lethal
concentrations, were observed to inhibit violacein pigment production by the C. violaceum CV026 and CV 31532 system and swarming motility of P. aeruginosa PAO1 and E. coli O157:H7. These results provided a foundation for the development of new antipathogens to circumvent issues related to antimicrobial resistance (Vattem et al., 2007). Upon ingestion, certain fruits are metabolized by the gut microbiota to produce compounds such as urolithins. These compounds have the potential to improve intestinal health by inhibiting the QS-
ACCEPTED MANUSCRIPT mediated virulence of pathogens including Yersinia enterocolitica (Table 3) (Espín et al., 2013; Truchado et al., 2012). Members of the Combretaceae plant family have been traditionally used to treat bacterial infections. Leaf and bark extracts of C. albiflorum have been tested for their QSI activities against virulence factors of P. aeruginosa strain PAO1 and pigment production by C.
PT
violaceum CV026. Here, catechin was found to exhibit QSI activity and inhibit biofilm
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formation by P. aeruginosa with no growth-inhibitory effects. Catechin reduced the
SC
expression of lasI and lasR by 20–40% and rhlI and rhlR by 38–44% (Vandeputte et al., 2010). Two other members of this plant family, Conocarpus erectus and Bucida buceras, are
NU
known for their QSI activities (Adonizio et al., 2006). Acacia nilotica has been used as an ayurvedic medicine because of its antioxidant and QSI activities. The hydrolyzed ethyl
MA
acetate fraction and hydrolyzed crude extract of the green pod at 0.4% concentration exhibited QS inhibition of the C. violaceum wild-type strain ATCC 12472, reducing pigment
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production by 60–80% (Singh (BN) et al., 2009). Traditionally, leaf extracts of the plant
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Terminalia catappa L. have been used for their antiseptic activity. The QSI activity of this leaf extract was detected through its ability to inhibit violacein pigment production in C.
CE
violaceum. A concentration of 62.5 μg/mL of the tannin-rich fragment of the extract caused a 50% reduction in the activity of the virulence determinant LasA of P. aeruginosa ATCC
AC
10145 and could completely inhibit the maturation of the biofilms of P. aeruginosa. This extract did not affect bacterial growth even at concentrations up to 962 μg/mL (Taganna et al., 2011). The pathogenicity of S. aureus is mediated by its agr and RAP/TRAP QSS. Hamamelitannin (2′,5-di-O-galloyl-d-hamamelose) found in the bark of witch hazel (Hamamelis virginiana) was reported to inhibit the RAP/TRAP QS of pathogens by blocking the TraP receptor. This increases the susceptibility of the S. aureus biofilm to antibiotics
ACCEPTED MANUSCRIPT (Brackman et al., 2016). Hydrastis canadensis, a perennial plant of the family Ranunculaceae, is a popular herbal medicine known for its anti-inflammatory and antimicrobial activities. It also produces bioactive compounds such as alkaloids (Scazzocchio et al., 2001). Extracts of this herb have been shown to inhibit the QS-Agr signaling system of S. aureus and inhibit α-toxin production (Cech et al., 2012). Malabaricone C derived from
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plants such as Myristica cinnamomea, Panax ginseng, Italian medicinal plants, orange, and
RI
broccoli has also been shown to act as a QSI (Chong et al., 2011; Koh et al., 2013).
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Syzygium aromaticum (clove) is a widely investigated spice used to treat dental caries and periodontal disease, asthma, and various allergic disorders. Extracts from the dried flower
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buds of S. aromaticum were shown to have QSI properties, as they inhibited pigment production of C. violaceum CV026 (the biosensor strain) and swarming motility in P.
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aeruginosa PAO1 (Husain et al., 2013; Krishnan et al., 2012). Clove bud oil inhibits QSmediated biofilm formation and disrupts the integrity of already-formed biofilms of P.
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aeruginosa. Clove oil at a concentration of 1% reduced biofilm formation by 85.3%, while
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increasing the dispersal of preformed biofilms by 50.4%. The treatment had no effect on the growth pattern of the pathogen. Decreases of 60%, 35%, and 24% were observed in
CE
swarming, swimming, and twitching motility, respectively. Exopolysaccharide and extracellular DNA release was also reduced by 91.9% and 65.5%, respectively. A 0.3-fold
AC
decrease in pqsA transcription was reported due to a decrease in kynurenine (61%), which is essential for the synthesis of the QS signal PQS. Porcine skin explants used to examine the ex vivo effects of 1% clove oil showed a significant decrease in bacterial load (Jayalekshmi et al., 2016). Syzygium cumini (Indian blackberry) is known for its anti-diabetic, antiinflammatory, and anti-bronchitis properties. The methanolic extract (1 mg/mL) of the fruit reduced the pigment-producing potential of C. violaceum by 82%, without effecting its growth. This fruit extract resulted in an 80% reduction in biofilm formation by the food-
ACCEPTED MANUSCRIPT borne pathogen, Klebsiella pneumoniae. The extract also increased bacterial sensitivity toward the antibiotic ofloxacine. Anthocyanin pigments were found to be the major components of the extract (Venkadesaperumal et al., 2016). QSI derivatives have reportedly been found in the extract of vanilla beans (Vanilla planifolia Andrews). A QSI that inhibited violacein production by C. violaceum CV026
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cultures has also been found in the extract (Choo et al., 2006). The effect of caffeine at 2.5
RI
mg/mL was initially found to efficiently retard the growth of bacteria such as E. coli,
SC
Enterobacter aerogenes, Proteus vulgaris, and P. aeruginosa (Dash and Gummadi, 2008; Norizan et al., 2013). Subsequently, caffeine was found to act as a QSI and a combination of
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caffeine and amoxicillin was reported to be effective against S. aureus (Esimone et al., 2008; Husain and Ahmad, 2015). The possibility of treating S. aureus infections with avellanin C
MA
produced by Hamigera ingelheimensis has been considered (Table 3) (Igarashi et al., 2015). Chinese herbs have long been used to treat various ailments such as pain, heart disease,
D
fever, and fractures. Panax notoginseng and Prunella vulgaris exhibited QSI activity against
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P. aeruginosa PAO1 and C. violaceum CV026 using highly diluted herbal extracts (Koh and Tham, 2011). Another herb, Scutellaria baicalensis Georgi, also exhibited significant QSI
CE
activity. It did not exhibit growth inhibition when tested on P. carotovorum subsp. carotovorum and E. coli cells, therefore lacking antibacterial potential. QS inhibition
AC
potential was recorded in potato slices infected with P. carotovorum, which showed reduced soft rot symptoms (Song et al., 2012). Crude extracts of a traditional Chinese herb Phyllanthus amarus exhibited anti-QS activities against pigment production by C. violaceum CVO26, bioluminescence in E. coli sensor strains, and virulence gene expression of P. aeruginosa PAO1. In P. aeruginosa, the plant extracts reduced pyocyanin production, swarming motility, and lecA::lux expression. Inhibition of lecA expression was significant at a higher concentration of 3 mg/mL, whereas 1 mg/mL was sufficient to inhibit swarming
ACCEPTED MANUSCRIPT (Priya et al., 2013). Given these findings, Phyllanthus amarus may act as an important source of anti-pathogenic drugs. Essential oils contain a variety of volatile fatty acids which have antiseptic properties and thus are useful in food and medicine. Studies have reported the use of these compounds as QSIs. Essential oils extracted from Colombian plants showed QSI activities against AHL-
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based QS organisms, possessing the biosensor plasmids pKR-C12 (Pseudomonas putida) and
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pJBA132 (E. coli). Most essential oil components show QSI activity against short-chain
SC
AHLs. Extracts of Lippia alba showed approximately 65% and 18% inhibitory activity against pKR-C12 and pJBA132, respectively, whereas Ocotea spp. extracts showed 25% and
NU
71–76% inhibition at 1.25 mg/mL, respectively (Jaramillo-Colorado et al., 2012). Carvone was one of the major components of the essential oils exhibiting antimicrobial activities
MA
(Shahat et al., 2008). Essential oils from Colombian species of the Piper genus exhibit QSI activities against C. violaceum CV026 with no significant effect on growth. IC50 values of
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45.6, 93.1, and 513.8 μg/mL were found for Piper bredemeyeri, P. brachypodom, and P.
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bogotence, respectively (Olivero et al., 2011). Rosemary and tea tree essential oils at 0.5 and 0.25 µL/mL showed 50–80% inhibition of pigment production in C. violaceum ATCC
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12472. Extracts of propolis and bee pollen also showed QSI activity but required a higher MIC of 1.14 and 8.67 µL/mL, respectively. These compounds also showed significant
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antimicrobial activities against the food-borne pathogens E. coli O157:H7 and Listeria monocytogenes. These pathogens form biofilms on food-processing equipment and are responsible for food spoilage (Alvarez et al., 2012). Vegetables from the Brassicaceae family have gained interest because of the anticancer and
antibacterial
properties
of
their
secondary
metabolites.
These
metabolites
(glucosinolates) and their enzymatic hydrolysates, isothiocyanates (sulforaphane), also exhibit QSI properties against P. aeruginosa and E. coli sensor strains. Inhibition of the AHL
ACCEPTED MANUSCRIPT receptor LasR at a concentration of 50 µM was observed for sulforaphane. The compound was able to inhibit biofilm formation by P. aeruginosa strain PAO1 at a minimum concentration of 12 µM. More than 70% inhibition of pyocyanin production was also observed with 100 µM of sulforaphane and erucin (Table 3) (Ganin et al., 2013). Ajoene, a sulfur-containing compound extracted from garlic, was found to be a strong
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antipathogen. It attenuated QS-controlled virulence such as that of rhamnolipid, a heat-stable
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hemolysin. Along with tobramycin, in vitro biofilms were also greatly affected and P.
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aeruginosa infection was significantly cleared in a mouse model (Table 3) (Jakobsen et al., 2012a). Similarly, iberin from horseradish inhibited QS of the opportunistic pathogen P.
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aeruginosa (Jakobsen et al., 2012b).
A phenolic compound extracted from the cider of the apple Malus domestica showed
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strong antimicrobial activity against different pathogens such as Chronobacter sakazakii (Table 3) (Fratianni et al., 2012). The polyphenol compound pyrogallol present in tea can
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regulate QS-mediated bioluminescence in V. harveyi (Ni et al., 2008). Ginger, Zingiber
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officinale, has been traditionally used as an important food component. Phenolic compounds present in ginger, such as [6]-gingerol, [6]-shogaol, and zingerone exhibited strong QSI
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activities against pyocyanin and violacein production by P. aeruginosa and C. violaceum, respectively. An isoxazoline derivative of [6]-gingerol and [6]-azashogaol, a derivative of
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[6]-shogaol synthesized chemically, was also very effective against the QS activity of P. aeruginosa (Kumar et al., 2014). Vegetables in the Cruciferae family including broccoli produce isothiocyanates such as sulforaphane and erucin, which have strong QSI properties that can inhibit virulence caused by P. aeruginosa (Ganin et al., 2013). Diterpene phytols evaluated at sub-MICs reduced biofilm formation by P. aeruginosa PAO1 by 74–84%. This reduction was higher than those recorded for treatments with streptomycin and ampicillin. Phytol at an MIC of 0.5 effectively
ACCEPTED MANUSCRIPT reduced other QS-mediated activities such as twitching, flagella motility, and pyocyanin activity (Table 3) (Pejin et al., 2015).
4.1.3 QSIs of animal origin A few studies have reported QSI activity by compounds of animal origin. Meat extracts
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such as those from turkey and beef patties, chicken breast, and beef steak showed 84.4–
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99.8% AI-2 signaling inhibition (Lu et al., 2004). AI-2 signaling of reporter strain V. harveyi
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BB170 was found to be inhibited by compounds present in ground beef (Soni et al., 2008). Various fatty acids such as linoleic, oleic, stearic, and palmitic acids isolated from poultry
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meat extracts are reported to exhibit QSI effects (25–99%) on the V. harveyi BB170 sensor strain. These fatty acids were reported to inhibit AI-2 mediated signaling at linoleic acid
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concentrations from 0.1–10 mM, causing 99% inhibition at 10 mM (Widmer et al., 2007). Cattle milk has long been known to contain a variety of essential nutrients and antipathogens.
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Raw cow and she-camel milk were also reported to contain anti-QSIs when tested against C.
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violaceum CV026 (Abolghait et al., 2011). Colostrum hexasaccharide isolated from mare colostrum was shown to degrade AHL signals and could inhibit QS-regulated biofilm
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formation and the production of virulence factors by S. aureus. This compound at 5 mg/mL, when used synergistically with 15 µg/mL of antibiotics such as clindamycin, linezolid, and
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erythromycin, increased the susceptibility of methicillin-resistant S. aureus (Srivastava et al., 2015). Phenolic compounds present in honey are effective in inhibiting virulence and biofilm formation by the opportunistic pathogen P. aeruginosa. However, the major limitations of the use of these therapeutic polyphenols is their lower solubility in water and inadequate bioavailability. A unique drug delivery system fabricated using selenium nanoparticles and polyphenols of honey resulted in the enhancement of QSI activity against P.
ACCEPTED MANUSCRIPT aeruginosa PAO1, both in vitro and in vivo. Bioinformatic analysis revealed that QSI acted by binding to the QS receptor LasR (Prateeksha et al., 2017). QS inhibitory enzymes such as acylases and paraoxanases have been isolated from animals such as rats, mice, zebrafish, and even humans. Acylase I from porcine kidney has been used in aquaculture as well as in the health care sector to inhibit AHL-mediated biofilm
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formation by A. hydrophila and P. putida (Dong and Zhang, 2005; Paul et al., 2009).
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Paraoxanases from human epithelial cells as well as those extracted from the serum of
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mammals such as rats, goat, bovine, and horses inhibit AHL-mediated QS in P. aeruginosa (Stoltz et al., 2007; Yang et al., 2005). Crude extracts of the freshwater sponge
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Ochridaspongia rotunda showed strong inhibitory activities with respect to pyocyanin in the range of 42–49%, which was more effective than that recorded for ampicillin. The extract
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also affected twitching and flagella motility. Thus, this extract has the potential to produce bioactive compounds for controlling P. aeruginosa biofilm (Pejin et al., 2014).
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The process of wound healing is impeded by biofilm-forming bacteria. Antibacterial and
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antibiofilm therapies must be combined to inhibit this process and allow for rapid healing. Natural and synthetic cathelicidin peptides have been reported to have antimicrobial and
CE
antibiofilm activities against S. aureus. The peptide functions by preventing cell adhesion as an antibiofilm molecule at low concentrations. Their helical characteristics were instrumental
AC
in expressing these antipathogenic properties and can be exploited for treating chronic infections (Dean et al., 2011; Strempel et al., 2015). Peptide LL-37 produced in humans acts by modulating the innate immune response. Additionally, it also has weak antimicrobial activity and inhibits bacterial biofilm in vitro. This effect on biofilm was exerted by the ability of peptide LL-37 to reduce the attachment of bacterial cells and influence the QSS of P. aeruginosa (Overhage et al., 2008).
ACCEPTED MANUSCRIPT In addition to enzymes, novel natural compounds are being investigated for their QSI activities. One such compound is a human sex hormone, estrone, which was reported to compete with AHL signals for receptors and reduce Ti plasmid transfer by A. tumefaciens. When tested using reporter strains, the compound also showed QSI activity against P.
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aeruginosa (Beury-Cirou et al., 2013).
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4.1.4 Antibodies as QSIs
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Monoclonal antibodies (MAbs) for AHL inactivation and sequestration were developed using lactam-containing haptens. Here, the linkers acted as analogs of AHL acyl chains
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(Kaufmann et al., 2006). The MAb RS2-1G9, specific for 3OC12HSL, acted as a QSI against pyocyanin production in P. aeruginosa (Kaufmann et al., 2006). This antibody effectively
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protected murine macrophages from the cytotoxic effects of the QS signal 3OC12HSL, which induces apoptosis (Kaufmann et al., 2008). Immunization of mice with bovine serum
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albumin-conjugated 3OC12HSL enhanced the survival of the animal from P. aeruginosa
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infection (Miyairi et al., 2006). The unique feature of this study was its demonstration that the inhibition of QS did not affect the bacterial population in the lung (Miyairi et al., 2006).
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MAb XYD-11G2 was shown to hydrolyze 3OC12HSL and inhibit pyocyanin produced by P. aeruginosa (Marin et al., 2007). Transition state analogs of AHL, i.e., sulfones, mimic the
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native substrate, binding to the enzyme with even higher affinity compared to that of the native substrate, which enables them to act as AiiA enzyme inhibitors (Kapadnis et al., 2009). In Gram-positive bacteria, peptides act as QS signaling molecules; antibodies against these peptide signals have been designed. Hapten AP4-5 mimics the QS signal, specifically AIP-4, which is produced by S. aureus (Park et al., 2007). MAb AP4-24H11 was produced by BALB/c mice immunized with proteins carrying AP4-5. The MAb showed high
ACCEPTED MANUSCRIPT specificity and strong binding affinity for AIP-4 over other QS signal molecules. AP4-24H11 modulated the production of exoproteins, virulence factors, and biofilm formation (Park et al., 2007). When used as a pre-treatment, AP4-24H11 protected all mice from death, while the combination of S. aureus and AP4-24H11 prevented lesion formation in murine infections (Park et al., 2007). This immunization strategy appears to be a useful approach for
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developing QSIs.
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4.1.5 Synthetic QSIs
Efforts have also been made to develop synthetic compounds to inhibit QS in pathogenic
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bacteria in human care sector. Thiazolidinedione (TZD) and its derivatives showed QSI activity against V. harveyi and P. aeruginosa, anti-bacterial activity against Gram-positive
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Streptococcus pneumoniae, and inhibition of biofilm formation by Candida albicans. Application of 20 μM of a TZD derivative, TZD-C8 ((z)-5-octylidenethiazolidine-2, 4-
D
dione), resulted in 70% biomass reduction in P. aeruginosa PAO1 biofilms with growth
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inhibition observed at a concentration of 20 mM. Inhibition of QS signal production and swarming motility was also observed in vitro. In silico docking predicted that TZD-C8 had
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very high affinity for LasI. Approximately 51 genes, including those of the pqsABCDE operon and lasI, were downregulated by this compound (Lidor et al., 2015).
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The QS signal molecule PQS is synthesized by P. aeruginosa by the condensation of anthranilate and β-keto-fatty acid. Analogs such as methyl anthranilate and halogenated anthranilate were reported to regulate the production of PQS and reduce virulent behavior (Calfee et al., 2001; Lesic et al., 2007). These compounds exhibited therapeutic properties, as they restricted the dissemination of the pathogen in a mouse model (Calfee et al., 2001; Coleman et al., 2008; Lesic et al., 2007). PQS production in P. aeruginosa can be inhibited by farnesol, a signal molecule produced by the fungal pathogen C. albicans. Additionally,
ACCEPTED MANUSCRIPT isoprenoids were found to act as effective QSIs (Cugini et al., 2007). It was shown that modifications in the AHL ring moiety can also produce effective antagonists. The cyclohexanone analog [N-(2-oxocyclohexyl)-3-oxododecanamide] of HSL (3OC12HSL) was effective as an antagonist of QS-mediated activities including biofilm formation by P. aeruginosa (Smith et al., 2003a). In the case of 3-oxo-C12-D10 (2-aminophenol), the
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aromatic ring was responsible for the QSI activity (Smith et al., 2003b).
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Nanoparticles are gaining importance as antipathogens. Incubation of silver nanoparticles
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(AgNPs) with biomass of the fungi Rhizopus arrhizus BRS-07 resulted in mycofabricated NPs (mfNPs). These mfNPs affected the transcription of lasI and lasR, which reduced AHL
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(C4HSL and C12HSL) production by 69–76%. The QSI did not affect growth but inhibited violacein pigment production by C. violaceum CV026 at 25 µg/mL and reduced virulence
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gene expression in the range of 15–96%. A higher concentration (50 µg/mL) of mfNPs was toxic to P. aeruginosa and human epithelial cells (Singh et al., 2015). A similar study
D
reported the treatment of C. ablicans infection with essential oil-AgNPs (Szweda et al.,
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2015). To inhibit QS and virulence caused by the human pathogen S. aureus, a synthetic QSI in the form of a macrocyclic peptide was loaded into degradable polymer nanofibers. QSI-
CE
loaded nanofiber coatings were able to strongly inhibit agr-based QS in a reporter strain of S. aureus for at least two weeks (Kratochvil et al., 2017). Numerous other synthetic compounds
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that were found to be important for inhibiting pathogenesis through QS inhibition were: (i) metal oxide nanoparticle drugs, active against methicillin resistant S. aureus (MRSA) and E. coli (Agarwala et al., 2014); (ii) azithromycin, active against α-hemolysin and biofilm formation by S. aureus (Gui et al., 2014); (iii) aryl-l-cysteine sulphoxides and related organosulphur compounds, active against V. harveyi BB170 and V. harveyi BB152 (Kasper et al., 2014); and (iv) FS8 and tigecycline, which prevented biofilm formation by Staphylococcus strains (Simonetti et al., 2013).
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4.1.6 Field trials 4.1.6.1 Human health Laboratory-scale studies have shown that fimbrolides or furanones can act as QSIs by preventing microbial adhesion. These compounds were assessed for their safety in clinical
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experiments against various pathogens such as P. aeruginosa, S. marcescens, S. aureus, etc.,
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which infected the contact lenses of guinea pigs and human volunteers. The trial period of 30
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days for animals and 24 hours for humans demonstrated the effectiveness of fimbrolidecoated contact lenses against bacterial adherence. A 67–92% reduction in bacterial adherence
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was recorded, supporting their use as antipathogens (Zhu et al., 2008). A clinical trial employing QSIs as therapeutics for treating cystic fibrosis in human
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patients was reported by Prof. Givskov and his team (Smyth et al., 2010). This pilot-scale trial was conducted using 656 mg/day of garlic oil macerate. This concentration was much
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lower than the dose toxic to humans. Here, 26 patients were monitored for eight weeks. The
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results were promising in terms of improved lung function, bodyweight, and reduced disease symptoms. Though a few patients did show abnormal liver function, and some were
CE
adversely affected to a small extent, the study was groundbreaking and encouraged further trials (Smyth et al., 2010). A clinical trial of azithromycin, a macrolide with QSI properties,
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was performed on intubated patients to test for activity against P. aeruginosa infection. This QSI lead to a significant reduction in QS-mediated pathogenicity (van Delden et al., 2012). However, the study also cautioned that the inevitable evolution of organisms remains a problem, in that they may develop resistance to QSIs (Köhler et al., 2010). Another strategy under consideration is a combination of antibiotics and QSIs in different model systems. Galleria mellonella larvae and C. elegans infected with P. aeruginosa and a B. cepacia complex showed better survival following combined treatment. A tobramycin and
ACCEPTED MANUSCRIPT cinnamaldehyde combination reduced the bacterial load in the lungs of BALB/c mice infected with Burkholderia cenocepacia compared to the use of antibiotics alone (Brackman et al., 2011). These studies are among the few clinical trials using QSIs reported in the public domain (Reuter et al., 2016). A garlic-based oral care formulation with QS-inhibitory and anti-inflammatory properties has been patented and is in-use by dentists. A carbonate-based
PT
QSI formulation has also been patented by Colgate-Palmolive (New York City, NY, USA)
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for oral care to inhibit biofilm formation (Grandclément et al., 2016).
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A considerable amount of work in recent years has also focused on the development of stable and specific QSI enzymes through genetic manipulations for direct administration to
NU
patients (Koch et al., 2014; Luo et al., 2014). An AHL acylase inhalation system has been developed using AHL-acylase (PvdQ) in a direct inhaler to quench the virulence of P.
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aeruginosa in cystic fibrosis patients. The freeze-dried enzymes incorporated in trehalose and inulin showed high stability during four weeks of storage even at 55 °C (Wahjudi et al.,
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D
2013).
4.1.6.2 Water treatment
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Treating water to make it suitable for drinking uses the innovative technology of a Membrane Bioreactor (MBR) (Meng et al., 2017; Siddiqui et al., 2015). However, bacterial
AC
biofilm formation causes the membrane to lose permeability. Given that bacteria use their QSS for biofilm formation (Berlanga and Guerrero, 2016), this network was targeted to prevent membrane biofouling. Porcine kidney acylase was applied to the MBR. This treatment retarded the trans-membrane pressure, indicating a role for the enzyme in alleviating membrane biofouling within the MBR (Yeon et al., 2009a). The QSI enzyme acylase, when immobilized on nanofiltration membranes, was also shown to mitigate membrane biofouling. The enzyme remained stable and 90% of its activity was retained for
ACCEPTED MANUSCRIPT approximately 20 cycles and up to 38 hours of operation in a continuous crossflow nanofiltration system (Kim et al., 2011). Membrane fouling of a submerged MBR was inhibited by encapsulating the bacteria within a porous vessel. The QSI activity of the bacteria in the porous vessel was observed to be steady for more than 100 days of MBR operation. This success was attributed to the continuous regeneration of bacteria with QSI
PT
activity and demonstrated energy-saving efficiency by reducing the rate of aeration required
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to operate the MBR (Jahangir et al., 2012). To enhance the life of the enzymatic system, a
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magnetic enzyme carrier (MEC) was used to immobilize AHL-acylase. Continuous use of MEC with 29 cycles of reuse was demonstrated in this study in an operational MBR (Yeon et
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al., 2009b). In contrast to the AHL-acylase used by other researchers, an E. coli strain genetically modified using AHL-lactonase from Rhodococcus sp. was added to a microbial
days of operation (Oh et al., 2012).
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vessel carrying functional bacteria. The MBR was found to function successfully for over 80
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To study the anti-biofouling effectiveness of QSIs for municipal wastewater treatment
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plants, an encapsulated lactonase producing bacteria (Rhodococcus sp. BH4) was installed in scaled-up MBRs. Immobilized Rhodococcus sp. BH4 in alginate beads was incorporated in a
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semi-pilot-scale 35-L MBR using synthetic wastewater conditions. After continuous operation for 95 days, the hydraulic resistance observed in the QSI-MBR was lower than that
AC
observed after 10–14 days of conventional MBR operation. Entrapped cells improved the dewaterability of the sludge i.e., reduced both the capillary suction period and the resistance to caking (Maqbool et al., 2015). The antibiofouling potential of bacteria was evaluated in both a single stage round as well as a three-stage round of MBR testing at the pilot-study scale. In single-stage MBR biofouling measured as total membrane potential, build-up was reduced by nearly 500% when QSI beads were used. The total bound exopolysachharide was reduced by 15% and a 7-fold reduction in total attached biomass per unit area of
ACCEPTED MANUSCRIPT biomembrane was observed for the QSI-MBR. The aeration intensity demand was also reduced to one-third that of conventional reactors, resulting in an approximately 60% reduction in energy consumption. The beads were also found to be stable during the operation (Lee et al., 2016).
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4.2 Medical devices
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Hospital-acquired infections have been reported to occur frequently with the use of
SC
medical devices (Neoh et al., 2017). Furanone – 5-Fluorouracil (5-FU), a pyrimidine analog was reported to inhibit QS-mediated pathogenicity in P. aeruginosa (Ueda et al., 2009).
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Functionalized catheters coated with this compound proved effective during clinical trials (Jacobsen et al., 2008; Walz et al., 2010). In a clinical study based on 960 adult patients from
MA
intensive care units, it was observed that central venous catheters coated with QSI 5-FU were less likely to cause infection than those coated with chlorhexidine/silver sulfadiazine
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(Jacobsen et al., 2008; Walz et al., 2010). However, the correlation between QSI and the
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reduction in bacterial contamination was not clearly stated. Antibacterial efficacy of the QSI furanone and the biofilm inhibitor dihydropyrrol-2-one were tested against P. aeruginosa
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PAO1 and S. aureus SA38. Adhesions of S. aureus and P. aeruginosa on glass surfaces coated with these inhibitors were reported to decrease by 71% and 93%, respectively (Taunk
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et al., 2016). A unique strategy to combine the low-fouling characteristic of poly(ethylene glycol) (PEG) and the QSI properties of the synthetic compound 5-methylene-1-(prop-2enoyl)-4-(2-fluorophenyl)-dihydropyrrol-2-one (DHP) was employed to design a PEGDAP (1,3-diaminopropane)-DHP coating to prevent biofilm formation. Assays conducted using P. aeruginosa and S. aureus showed that PEGDAP-DHP in different ratios led to significant reduction in cell adhesion and biofilm formation (Ozcelik et al., 2017). Efforts to prevent catheter-associated urinary tract infections by C. albicans resulted in the development of a
ACCEPTED MANUSCRIPT delivery system for sustained release of QSI–TZD-8. In this system, varnishes could be retained on the catheters for eight days and they were effective in reducing biofilm formation (Shenderovich et al., 2015). The effects of norspermidine on biofilm formation and its eradication in the case of P. aeruginosa PAO1 warrant further commentary. A low dose of 0.1 mM initiated the inhibition
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of biofilm formation, whereas 1.0 mM was effective for eradicating a mature biofilm. Other
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advantages were a 45–69% decrease in QS-mediated pyocyanin, elastase, and protease
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activities (Qu et al., 2016). Studies of the biotechnological applications of these results provided useful insights; for instance, catheters immersed in this compound did not allow
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biofilm formation, preventing device–related infections (Qu et al., 2016). Polyhydroxyalkanoates (PHAs), commonly known as bioplastics, have been introduced as
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antibiofilm agents. Modifications of PHA resulted in the production of molecules with antibacterial and antiviral properties (Radivojevic et al., 2016). Modification of the
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monomeric composition of PHA involved regulating the feed-enabled synthesis of a polymer
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composed of monomers of (R)-3-hydroxyoctanoic acid, which was then modified to produce a library of compounds. Of these compounds, (E)-oct-2-enoic and (R)-3-hydroxyoctanoic
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acids were able to inhibit the QS-mediated pyocyanin production in P. aeruginosa PAO1 (Radivojevic et al., 2016).
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Biofilm formation can be avoided by reducing bacterial adhesion on an implant (Gallo et al., 2014). Membranes of PHA-homopolymers and co-polymers such as poly(3hydroxybutyrate-3-hydroxyhaxanoate) have been used to prevent biofilm formation on wounds and implant surfaces. These sheets, when loaded with lysozyme at a rate of 16.1 µg per 9.5 mm3 discs, were effective in inhibiting biofilm formation (Kehail and Brighan, 2018). Coating of the implants with the PHA copolymer enhanced and stabilized drug release within a given time period (Rașoga et al., 2017; Rodríguez-Contreras et al., 2017).
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5. Challenges in implementing QSI 5.1 The rise and fall of antibiotics The discovery of antibiotics was a boon for patients suffering from fatal diseases (Kalia et al., 2007). However, a strong selective pressure generated by the indiscriminate use of
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antibiotics to treat diseases has led to the emergence of drug-resistant bacterial strains (Ciofu
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et al., 1994). Many new antibiotics were developed to counter bacterial resistance but none of
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these lasted more than ten years. These repeated failures caused reluctance on the part of pharmaceutical companies to invest time and money in developing novel antibiotics (Kalia et
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al., 2007). It proved to be an opportunity for researchers to look for novel strategies to counter bacterial infections. The discovery of QSIs and their initial success has fueled efforts
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to improve their efficacy and diversify their applications. Unlike antibiotics, QSIs are unique in that they interfere with virulent gene expression in bacteria without affecting their growth.
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However, the apprehension already exists that these compounds may also generate selective
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pressure and provoke bacteria to develop resistance. At present, there is little evidence to support this concern; however, the possibility cannot be completely ruled out (Defoirdt et al.,
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2010b; Diggle et al., 2007; García-Contreras et al., 2013, 2016; Kalia et al., 2014; Koul et al.,
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2016; Maeda et al., 2012).
5.2 Emergence of resistance to QSIs Evidence supporting the possibility of the emergence of resistance to QSIs in bacteria has been generated by the use of QS-mutants. Mutants of P. aeruginosa showing greater efflux of QSI-brominated furanone (C30) were reported to be among the potential mechanisms to counter QS disruption (García-Contreras et al., 2015; Maeda et al., 2012). In fact, cystic fibrosis patients were reported to be infected by bacterial isolates carrying these efflux-
ACCEPTED MANUSCRIPT enhancing mutations and showed resistance to this QSI disruption (Maeda et al., 2012). This indicated that bacteria may be genetically equipped with arsenals able to counter QSIs. Under stress conditions, certain bacteria act as “social cheaters” in that they stop responding to the QSS, thereby affecting the efficacy of QSIs (Sandoz et al., 2007; Tay and Yew, 2013). However, since these mutants show reduced fitness, their chances of survival are expected to
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be low (Gerdt and Blackwell, 2014). Likelihood of the emergence of resistance to QSIs is
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also influenced by the mechanisms of action of the QSIs themselves.
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Presence of multiple QSS in certain microbes enhances the likelihood that heterodimers of transcriptional regulators will bind to promiscuous promoters, enabling bacteria to express
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genes to counter a wider range of environmental stresses, including those caused by QSIs (Decho et al., 2010; Koul and Kalia, 2017). The variability in the specific activities of AHL
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synthases in strains of E. carotovora and the multiplicity of LuxR signal receptor homologs in Burkholderia mallei are latent features which further support the bacterial potential to
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develop resistance to QSIs (Brader et al., 2005; Case et al., 2008). In P. aeruginosa, the QSS
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-rhl and -las are essential for biofilm formation and their disruption depends upon the antibiotics used and the host immune system (Bjarnsholt, 2005). The PQS system of P.
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aeruginosa acts to regulate programmed cell death, which induces the release of extracellular DNA. This unique system proves beneficial for the survival of the other members of the cell
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population (Hazan et al., 2016). The use of enzyme-based QSIs which act on QS signals outside the bacterial cell have been suggested to be ideal candidates (Defoirdt et al., 2010b; García-Contreras et al., 2013; Guendouze et al., 2017; Kalia and Purohit, 2011). The apprehension remains that bacteria may become provoked to produce larger quantities of QS signal molecules. In fact, it has been shown that QS-mediated swarming motility in Serratia liquefaciens and a LuxRregulated PluxI-gfp (ASV) fusion in a mouse model inhibited by QSI-brominated furanone
ACCEPTED MANUSCRIPT could be reversed by exogenous addition of AHLs (Givskov et al., 1996; Hentzer at al., 2003). Hence, we must ensure that enzymes with high hydrolytic activity and stability be employed. Although these hydrolytic enzymes have a very broad spectrum of activity, the chance exists for bacteria to react by modifying their QS signal molecules. Bacteria also have the potential to modify their LuxR receptors to improve affinity for QS signal molecules
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(Collins et al., 2005; Hawkins et al., 2007), requiring that the QSI enzymes be modified to
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detect AIs even at very low concentrations. Another challenge in treating these infectious
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bacteria is that their QS-mediated pathogenicity occurs at high cell density; therefore, the ability to detect these bacteria and their QS signals at low densities, i.e., before the onset of
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disease, is crucial.
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5.3 QSIs and the microbiome
A major shift in the microbial consortium present in the epibiotic microbiome was
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observed in healthy Caribbean corals as well as those affected by Black Band Disease
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(BBD). The dominant bacteria in the epibiomes were strains of Halomoas, Moritella, and Renibacterium, whereas the black band consortia were dominated by cyanobacterium
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Roseofilum and uncultured genera of Rhodobacteraceae and Bacteroidales, Desulfovibrio and Fusibacter, respectively. The QSI lyngbic acid was produced in the diseased state and
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acted as a natural antagonist of the QSS (CqsS/CAI-1) of Vibrio spp., which co-occur with Rosefilum reptotaenium within the BBD consortia (Meyer et al., 2016). Members of the microbial community present in the human body, such as Enterobacter sp. strain T1-1, have been reported to operate QS through AHLs (Yin et al. 2012a). The human gut microbiome is inhabited by strains of Klebsiella, Salmonella, Escherichia, and Enterobacter, which have a single LuxR homolog, SdiA, and do not possess acyl-HSL synthase, indicating that these organisms operate their QSS via eavesdropping on AHLs
ACCEPTED MANUSCRIPT produced by others such as Y. enterocolitica (Swearingen et al., 2013). In this scenario, QSIs can be expected to influence human health, including metabolic disorders, by affecting the gut microbiome (McCarthy and O’Gara, 2015; Hur and Lee, 2015). Dietary substances present in foods such as grapefruit, coffee, and garlic can thereby influence the QSS and
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possibly have medicinal impact (McCarthy and O’Gara, 2015).
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5.4 The ideal QSIs
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To prevent and minimize the evolution of QSI resistance, a few criteria have been established for their selection. QSIs should have: (i) low molecular weight; (ii) high
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specificity; (iii) no adverse effect on hosts; (iv) high stability; (v) resistance to degradation by host metabolism; and (vi) no negative influence on host microbiome (Hentzer and Givskov,
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2003; Rasmussen and Givskov, 2006; Rasmussen et al., 2005; Vattem et al., 2007). The efficacy of these QSIs must be demonstrated not only in sensor strains but also on clinical
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isolates. In addition, regulatory concerns must be addressed. The increasing range of QSIs is
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likely to aid in the development of innovative devices. The efficacy of QSIs against bacterial infections has been demonstrated largely using animal models; these studies are being
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extended to develop medical devices against bacterial infections in order to enlarge the scope of the therapeutic arsenal against pathogenic bacteria. QSIs can be expected to have
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numerous biotechnological applications in yet unexplored areas of economic importance (Bzdrenga et al., 2017).
6. Conclusion The field of QS-mediated infectious disease has been the focus of researchers worldwide. To counter the repeated failures of antibiotics against infectious diseases, efforts have shifted to using QSIs as antipathogens. Regulating bacterial infections in aquaculture by interfering
ACCEPTED MANUSCRIPT with QSS is an effective approach for reducing economic losses incurred in this industry. The potential of this therapy is promising since most of these compounds are produced naturally by organisms. Since the most widely reported QSS operate through AHLs, targeting them to inhibit bacterial pathogenesis becomes as obvious choice. Inactivation of AHLs released into the milieu has been realized to be better since it dioes not impose any selective pressure on
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the pathogen. Inactivation of AHLs through AHL lactonases and AHL-acylases has been
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widely reported (Kalia, 2013; Kalia and Purohit, 2011, Kumar et al., 2013). AHL-lactonases
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are preferred over AHL-acylases, as these are not limited by the acyl chain length and have a broad substrate range with specificity for (s)-configuration and long N-acyl substitutions
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(Fuqua et al., 2001; Liu et al., 2013; Thomas et al., 2005; Wang et al., 2004; Yin et al., 2012b). Here, the highest potential for application of AHL-lactonases as QSIs appears to lie
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in the use of Bacillus spp.: B. sonorensis, B. subtilis, and B. thuringiensis (Chu et al., 2014; Defoirdt et al., 2011b; Dong et al., 2000, 2001, 2002, 2004; Huma et al., 2011; Liu et al.,
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2013; Momb et al., 2008; Niu et al., 2014; Pan et al., 2008; Thomas et al., 2005; Yin et al.,
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2012b; Zhou et al., 2006; Zhu et al., 2006). AHL lactonase activities from a wide range of Bacillus spp. were reported to be in the range of: (i) 480-674 pmol/h/unit OD600 of the
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bacterial culture (Dong et al., 2002; Piper et al., 1993), and; (ii) 4.98-6.56 μg/h per 109 CFU/ml (Chan et al., 2010). Kinetic analysis of lactonases has revealed stronger catalytic
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efficiency for AHLs with: (i) completely reduced acyl chains, and (ii) long acyl side chains (Liu et al., 2013, Momb et al., 2008, Wang et al., 2004). Expression of AHL lactonases in different bacterial and eukaryotic hosts (aquaculture animals, zebrafish and Artemia shrimp) has been effective in reducing diseases caused by different pathogens (A. hydrophila, E. carotovora, V. campbellii) (Chu et al., 2014; Defoirdt et al., 2011b; Niu et al., 2014; Chen et al., 2010; Dong et al., 2000; Molina et al., 2003; Pan et al., 2008; Ulrich, 2004; Zhou et al., 2006). Among plant sources of QSIs, coumarin shows great potential in that it can act against
ACCEPTED MANUSCRIPT diverse QS signal molecules. Other strategies likely to prove effective are mechanisms for enhancing host secretion systems such as stress hormones. Large-scale trials are needed before we can actualize the benefits of this approach. Rather than developing novel antibiotics, studies should be aimed at searching for novel bioactive molecules, nanoparticles, etc., that can act both as antimicrobials and
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antipathogens. Efforts are being made and the concept is gaining momentum, as is evident
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from the wide variety of research activities related to this topic, including antimicrobials
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(López et al., 2017; Sajid et al., 2015), natural products and bioactive molecules (Blunt et al., 2015; Ray and Kalia, 2017; Saini and Keum, 2017; Sharma and Jangid, 2015; Thakur et al.,
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2017), nanotechnology (Wadhwani et al., 2016), and microbial diversity (Pooja et al., 2015; Sharma and Lal, 2017).
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The large reservoir of basic studies on the potential applications of QSIs in protecting humans from infectious diseases has boosted the morale of the scientific community.
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However, the real test lies in large scale trials on the effects of QSIs on infectious diseases.
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So far, limited effort has been directed to the use of QSIs. For the time being, we may have to manage with the use of phytonutrients as rich dietary sources of QSIs, the use of bioactive
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compounds to cause pseudo-induction of QS and expose bacteria to the immune system, and the eradication of biofilms to render pathogens susceptible to low doses of antibiotics.
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Although QSIs are giving hope to human beings for getting protected from bacterial pathogens, however, we should not overlook the fact that QSIs are not acting in the interest of bacteria. As bacteria have the necessary genetic machinery to counter any environmental stress, they may thus evolve to counter this inteference with their metabolic activities.
Acknowledgements
ACCEPTED MANUSCRIPT This work was supported by Brain Pool grant (NRF-2018H1D3A2001746) by National Research Foundation of Korea (NRF) to work at Konkuk University. This research was supported by Basic Science Research Program (2017R1A2B3011676, 2017R1A4A1014806) and
by
the
Intelligent
Synthetic
Biology
Center
of
Global
Frontier
Project
(2013M3A6A8073184) through the National Research Foundation of Korea (NRF) funded
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by the Ministry of Science, ICT & Future Planning.
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Figure Caption
Fig. 1. Application of quorum sensing (QS) inhibitors for protecting: (i) plants, (ii) animals,
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and (iii) human beings from diseases caused by pathogenic bacteria through QS system.
ACCEPTED MANUSCRIPT Table 1. Biotechnological applications of quorum sensing inhibitors in aquaculture
Quorum sensing
Source
Target
Mode of activity
Applications
References
Tetradecanoyl-L-
Fresh water algae
Aeromonas
Block quorum
Protection of burbot
Natrah et
Homoserine Lactone
- Chlorella
hydrophila and
sensing (QS)
(Lota lota) larvae
al., 2012
(C14-HSL) / (10 µM)
saccharophila and
A. salmonicida
signal molecule
from Aeromonas
inhibitors / (Effective
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Conc.)
synthesis, receptor
reinhardtii
interaction
C. saccharophila
Vibrio harveyi,
/ (1 µg/L)
CCAP211/48
QS antagonist
infection
Protection of fresh
Natrah et
Chromobacteriu
water animals from
al., 2011
m violaceum
Vibrio infection
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Secondary metabolites
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Chlamydomonas
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CVO26,
Escherichia coli
Brachymonas
V. harveyi, V.
Degrades QS
Protection of
Dang et al.,
(PHB) / (25 mM, 10
dentrificans,
campbellii
signal molecule -
Artemia from
2009;
mg/L, NA)
Bacillus sp.,
LMG21363
AHL
pathogens
Defoirdt et
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Polyhydroxybutyrates
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JB523
al., 2007a;
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Bacillus circulans
PHB Depolymerase /
Acidovorax spp.
(1.25 g/L)
Halet et al., 2007 V. harveyi
Degrades QS
Protection of
Liu et al.,
and
signal molecule -
Artemia from
2010
Ochrobactrum
AHL
pathogens
Inactivates QS
Digestive enzyme
Cao et al.,
signal molecule –
resistant and
2012
AHL
thermostable
spp. AHL lactonase / (100
Bacillus sp. strain
mg/L)
AI96
A. hydrophila
ACCEPTED MANUSCRIPT lactonase as fish feed to prevent infections AHL lactonase / (200
Bacillus sp. QSI-1
µg/L)
A. hydrophila
Inactivates QS
Probiotic to reduce
Chu et al.,
YJ-1
signal molecule –
pathogenicity in
2014
AHL
zebrafish (Danio
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rerio)
Labrenzia
C. violaceum
Inactivates QS
µM)
alexandrii
CV026
signal molecule –
Protection of fishes
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AHL lactonase / (0.5
Ghani et al., 2014
Aquculture
inhabiting
pathogens such
bacteria,
as: Aeromonas.
Flaviramulus
Edwardsiella,
ichthyoenteri
haloperoxidase / (2
(Laminaria
µM)
digitata)
Cinnamaldehyde /
Bark of cinnamon
(100 µM)
trees
signal molecule –
aquaculture
2015
Deactivate N-β-
Inactivation of QS
Syrpas et
CVO26, E. coli
ketoacylated
mediated virulence
al., 2014
JB523
HSLs (AHLs)
of pathogens
V. harveyi
Decreases DNA
Protection of
Brackman et
binding ability of
Artemia shrimp
al., 2008
Decreases DNA
Protection of larvae
Pande et al.,
binding affinity of
of Macrobrachium
2013
LuxR
rosenbergii, (Giant
C. violaceum
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Zhang et al.,
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Brown algae
AHL
Bark of cinnamon
LuxR V. harveyi
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µM)
Use as a probiotic in
and Vibrio spp.
Vanadium
Cinnamaldehyde / (1
Inactivates QS
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Fish intestine
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AHL lactonase / (NA)
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AHL
trees
fresh water prawn) from infection and mortality Pyrogallol / (10 mg/L)
Emblica officinalis
V. harveyi
Disrupts QSS
Protection of brine
Defoirdt et
shrimp and giant
al., 2013
river prawn from
ACCEPTED MANUSCRIPT infection Curcumin / (100
Plant
Vibrio spp.
µg/ml)
Attenuates QS
Treatment of nauplii
Packiavathy
mediated
of A. franciscana
et al., 2013
virulence Coumarin/ (1.36 mM)
Plant
V. anguillarum,
Inhibit biofilm
Protection of
Gutiérrez-
E. tarda
formation,
salmonid fish
Barranquero
PT
production of
et al., 2015
phenazines,
Hesperozygis
A. hydrophila
µg/ml)
ringens, Ocimum
NU
gratissimum and O. americanum Synthetic
V. harveyi
MA
Brominated furanones
-
SC
Essential Oil / (100
Thiophenones / (0.25
PT E
Synthetic
Sutili et al.,
catfish (Rhamdia
2015
quelen)
Protection of brine
Defoirdt et
signal
shrimp A.
al., 2007b
transduction
franciscana from infections
Vibrionaceae and
Antagonistic to
Prevention of white
Certner and
Flavobacteriacea
AHL
band disease on
Vollmer,
coral reefs
2018
Antagonistic
Protection of brine
Yang et al.,
binding to LuxR
shrimp larvae
2015
-
Brackman et
e members V. harveyi
analogues of
AC
µM)
Synthetic
CE
Furanone / (50 µM)
Protection of silver
Interferes with QS
D
/ (50 mg/L)
RI
swarming motility
furanones
receptors
Thiazolidinediones/
Structurally
V. harveyi
Antagonistic
(12.2-100 µM)
resembled N-
binding to LuxR
acylaminofuranon
receptors
al., 2013
es AHL analogues / (NA)
Pseudomonas sp.
Fish pathogens:
Blocks AHL
Use as a probiotic
Fuente et
strain FF16
Flavobacterium
synthesis
candidate for the
al., 2015
and Raoultella
psychrophilum,
salmon farming
ACCEPTED MANUSCRIPT planticola strain
Vibrio
industry
R5B1
anguillarum, and A. hydrophila
A peptide 5906 / (NA)
Escherichia coli
Edwardsiella
Inhibits AI-2
Protection of fish
Sun and
strain
tarda
activity
from
Zhang, 2016
DH5α/p5906
PT
Bacillus sp.
Pseudoalteromon
Inhibits biofilm
Improvement of
Ganesan et
AMBG1 and
as sp. AMGP1
formation
larval settlement of
al., 2010
RI
Biofilm exudate / (NA)
Edwardsiellosis
AMGM1 Microbes from
Opportunistic
culture EC3 and EC5 /
Penaeus
pathogens
(1 mg/L)
vannamei shrimp
AC
MA
CE
PT E
D
gut
Degrades AHLs
NU
Enrichment bacterial
SC
Macrococcus sp.
mussel – Perna canaliculus Improvement of the
Tinh et al.,
survival of first-
2008
feeding turbot larvae (Scophthalmus maximus L.)
ACCEPTED MANUSCRIPT Table 2. Biotechnological applications of quorum sensing inhibitors against plant pathogens
Quorum sensing
Source
Target
Mode of
inhibitor
Applications
References
Prevention of
Dong et al., 2000,
activity Pseudomonas
Pectobacterium
Inactivates
(AHL) Lactonase
fluorescens
carotovorum
quorum
potato and
sensing (QS)
tobacco plants
2001
RI
PT
Acylhomoserine lactone
signal
SC
molecule – AHL
tumefaciens
6276
NU
Erwinia strain
Bacillus
Erwinia amylovora
AHL Lactonase
Bacillus cereus
CE
AC
AHL Lactonase
PT E
D
AHL Lactonase
Agrobacterium
MA
AHL Lactonase
Reduction of
Carlier et al.,
signal
virulence in plant
2003
Inactivates QS
Reduction in fire
Molina et al.,
signal
blight disease of
2005
molecule –
apple
molecule – AHL
AHL Erwinia
Inactivates QS
-
Zhao et al., 2008
Inactivates QS
Prevention of
Ban et al., 2009
signal
Amorphophallus
molecule –
konjac from soft
AHL
rot disease
Inactivates QS
Prevention of
Vanjildorj et al.,
signal
Chinese cabbage
2009
signal molecule – AHL
Amorphophallus
P. carotovorum
konjac
AHL Lactonase
Inactivates QS
Bacillus
P. carotovorum
ACCEPTED MANUSCRIPT molecule –
(Brassica rapa)
AHL
from soft rot disease
Bacillus spp. and P. P. carotovorum
Inactivates QS
Prevention of rot
Helman and
fluorescens
signal
and gall
Chernin, 2015
molecule –
symptoms
AHL Bacillus
Burkholderia
Inactivates QS
Prevention of
thuringiensis
glumae
signal
disease - seedling
RI
AHL Lactonase
PT
AHL Lactonase
SC
molecule –
Cho et al., 2007
rot of rice
AHL
Clove oil
P. carotovorum
NU
Phenolic compounds:
and P. aroidearum
Reduction in
ExpI/ExpR
pathogenicity of
proteins
P. aroidearum
γ- caprolactones
Rhodococcus
PT E
stimulating AHL
AC
glucopiericidin A
CE
Lactonase
Piericidin A and
N,N′-bisalkylated
D
MA
carvacrol and eugenol
Bind to
Streptomyces
and P. carotovorum
Pectobacterium
Inactivates QS
Protection from
atrosepticum
signal
soft rot of potato
Cirou et al., 2011
molecule – AHL Competes with
Protection from
xanthocidicus
AHL binding
soft rot of potato
KPP01532
site
Synthetic
Joshi et al., 2016
Erwinia carotovora
P. atrosepticum
imidazolium salts
Kang et al., 2016
Antagonistic
Inhibition of
Des Essarts et al.,
binding to
blackleg and soft-
2013
LuxR
rot diseases of
receptors
potato plants and tubers
Compound J8-C8
Synthetic
B. glumae
Competetively
Inhibition of
Chung et al.,
inhibits QS by
virulence and rice
2011
ACCEPTED MANUSCRIPT binding to TofI
grain rot by the pathogen
Curcuma longa
Competetively
Inhibition of
Chung et al.,
inhibits QS by
virulence and rice
2011
binding to
grain rot by the
TofR
pathogen
Pseudomonas
Downregulate
Inhibition of
Rudrappa and
aeruginosa PAO1
the production
virulence in plant
Bais, 2008
of AHLs
(Arabidopsis
Plant leaves
Pseudomonas
MA
Bacterial epiphytes
NU
SC
RI
Curcumin
B. glumae
PT
Compound E9C-3oxoC6 Synthetic
CE
PT E
D
syringae
Plants
(Caenorhabditis elegans) models
Premnature
Suppression of
Dulla and
induction of
swarming motility
Lindow, 2009
QS
and disease of the leaf
Suppresses
Reduction in
ahll. limiting
disease lesions
Dulla et al., 2010
of iron A. tumefaciens
amino acid) and salicylic acid
animal
the availability
AC
GABA (the nonprotein
P. syringae
thaliana) and
Degrades
Transgenic plants
Chevrot et al.,
AHLs
less sensitive to
2006; Yuan et al.,
A. tumefaciens
2007; 2008
infection Free L-proline
Synthetic
A. tumefaciens
Antagonizes
Transgenic plants
Haudecoeur et al.,
plant-GABA
less sensitive to
2009
defense
A. tumefaciens infection
Carbamoylphosphate
Pseudomonas spp.
Xanthomonas
Degrades
Reduction in
Newman et al.,
ACCEPTED MANUSCRIPT campestris
Xylella fastidiosa
Diffusible
disease severity in
signal factor
mustard and
(DSF)
cabbage leaves
Degrades DSF
Reduction in
2008
disease severity in grape stem X. fastidiosa
Restricts QS
Reduction in
Lindow et al.,
mediated
disease severity in
2014
mobility
grape and severity
PT
Freedom grape
Citrus plants
Xanthomonas citri
AC
CE
PT E
D
MA
NU
DSF
SC
RI
DSF
of Pierce’s disease
Restricts QS
Reduction in
Caserta et al.,
mediated
disease severity in
2014
mobility
Citrus sinensis and Carrizo citrange plants
ACCEPTED MANUSCRIPT Table 3. Biotechnological applications of quorum sensing inhibitors against human pathogens
Quorum
Source
Target
Mode of activity
Applications
Garlic (Allium
Pseudomonas
Down-regulate
sativum L)
aeruginosa
quorum sensing (QS) infections inhibiting
References
sensing
Iberin
Horseradish
P. aeruginosa
Broccoli
P. aeruginosa
PT E
(Brassica
Ginger extracts
P. aeruginosa
CE
(Curcuma
AC
longa)
O-glycosylated
Orange extracts
flavanones
Polyphenols
Apple extracts
Jakobsen et al., 2012a
RI
formation
Antagonist LasIR and Treatment of
Antagonists LasR
D
extracts
Phenolics
and rhlAB)
MA
rusticana)
oleracea)
virulence and biofilm
RhlI/R
(Armoracia
Sulforaphane
genes (lasA, chiC,
NU
extracts
Treatment of
SC
Ajoene
PT
inhibitors
Jakobsen et al., 2012b
infections inhibiting virulence and biofilm formation Treatment of
Ganin et al., 2013
infections inhibiting virulence and biofilm formation
Down-regulates
Inhibition of
LasI by binding of
pyocyanin and other
long acyl chains of
virulence factors
the compounds to
production
Kumar et al., 2014
LasR Yersinia
Induce QS
Inhibition of
enterocolitica
regulatory genes,
swimming motility
yenR (regulation of
and biofilm
AHLs) and flhDC
maturation in the
(motility)
enteropathogen
Inhibits perception
Food preservation,
E. coli,
Truchado et al., 2012
Fratianni et al., 2012
ACCEPTED MANUSCRIPT (Malus
Cronobacter
of AHLs by LuxR
antibacterial drugs
domestica var.
sakazakii
type signal receptors
Metabolism of
Y.
Inhibits AHL
Improvement of
Espín et al., 2013;
Ellagitannins
enterocolitica
synthesis through
intestinal health
Truchado et al., 2012
from fruits by
YenI/ YenR
gut microbiota
inhibition
Essential oils
Candida
Propolis and
from Lavender,
albicans, C.
Ag-TiO2
Lemon, Tea
glabrata,
nanoparticles
tree, Basil,
C. krusei
-
NU
Geranium,
MA
Cinnamon and Clove
V. harveyi
Modulate response
Inhibition of biofilm
seeds (Citrus
BB120
regulator gene luxO,
formation
PT E
D
Sour orange
aurantium L.)
Fenugreek seeds
inhibiting AI-2 mediated QS Inhibition of
extract
PAO1,PAF79;
production
virulence factor
(Trigonella
Aeromonas
production in human
foenum-
hydrophila
as well as aquatic
graecum L.)
WAF38
pathogens
Malagasy plant
P. aeruginosa
Reduces signal
Reduction in
Vandeputte et al.,
(Combretum
PAO1
perception by RhlR
virulence and
2010, 2011
albiflorum) Chamaemelum nobile flower extract
•
Inhibits AHL
AC Flavanoids
Vikram et al., 2011
P. aeruginosa
CE
Caffeine
Szweda et al., 2015
infections
Thyme,
Limonoids
Treatment of fungal
RI
Essential oils,
SC
Urolithins
PT
Annurca)
C. nobile
Husain and Ahmad, 2015
biofilm formation P. aeruginosa
-
Antibacterial role in• fighting infections
Kazemian et al., 2015
ACCEPTED MANUSCRIPT Kalanchoe
Kalanchoe
leaves extract
blossfeldiana
P. aeruginosa
Interferes with AHL
Inhibition of
production
virulence by drug
•
Sarkar et al., 2015
resistance strains freshwater
P. aeruginosa
Inhibit biofilm
Treatment of
sponge
PAO1
formation,
infections through
Ochridaspongia
twitching, flagella
medical foods
rotunda
motility and
P. aeruginosa
Inhibit biofilm
vegetables
PAO1
formation,
SC
Green
(chlorophyll
twitching, flagella
component)
motility and
NU
Phytols
Treatment of
Pejin et al., 2015
RI
pyocyanin activity
Pejin et al., 2014
PT
Extract
infections through medical foods
pyocyanin activity
Hamigera
Staphylococcu
ingelheimensis
s aureus
Inhibits agr
MA
Avellanin C
NRRL 29060
signalling pathway
Treatment of
•
staphylococci infections
Jelly fungi
Chromobacter
Binds to the active
Food preservatives,•
(melanin,
(Auricularia
um violaceum
site of LuxR type
antimicrobial drug
melanoid,
auricula)
PT E
CE
Quercetin
D
Pigments
pheomelanin)
Edible lichen
C. albicans
AC
(Usnea
longissima)
Zhu et al., 2011
AHL receptors
Induces farnesol
Treatment of
production known to
candidiasis by
regulate QS
sensitizing the
mediated virulence
fungus to
and biofilm
fluconazole (FCZ),
formation
antifungal drug
Cyclic
Lactobacillus
S. aureus
Down-regulate
Treatment of
dipeptides
reuteri RC-14
MN8
RNAII and RNAIII
menstrual-
transcripts from agr
associated toxic
locus
shock syndrome
(vaginal isolate)
Igarashi et al., 2015
Singh et al., 2015
•
Li et al., 2011
ACCEPTED MANUSCRIPT Engineered
Sulfolobus
variant of
P. aeruginosa
•
Degrades lactone
Reduction in
solfataricus
ring of 3-oxo-C12
Pneumonia severity
hyper-
(extremophilic
AHLs with
caused by
thermostable
archaea)
improved catalytic
Pseudomonas
efficiency
infection
lactonase SsoP
Hraiech et al., 2014
Thermostable
Geobacillus
Acinetobacter
Degrades lactone
lactonase
kaustophilus
baumannii
ring of AHLs
Chow et al., 2014
RI
catalytic efficiency,
S. aureus
Degrades AHLs
CE
PT E
D
MA
hexasaccharide
NU
Colostrum
AC
Pathogen inhibition by increased
SC
HTA426
Colostrum
PT
ox
stability, and substrate range of enzyme Inhibition of virulence and biofilm formation by antibiotic resistant strains
•
Srivastava et al., 2015
ACCEPTED MANUSCRIPT Quorum Sensing Inhibitors as Antipathogens: Biotechnological Applications
Vipin Chandra Kaliaa*, Sanjay K. S. Patel a, Yun Chan Kang b, Jung-Kul Lee a*
Department of Chemical Engineering, Konkuk University, Seoul 05029, Republic of Korea
b
Department of Materials Science and Engineering, Korea University, Anam-Dong,
RI
PT
a
Corresponding author:
NU
*
SC
Seongbuk-Gu, Seoul 02841, Republic of Korea
PT E
D
MA
E-mail: [email protected] (V.C. Kalia) or [email protected] (J-K. Lee)
CE
Highlights
Quorum sensing (QS) mediated pathogenicity in aquaculture, plants, and humans
AC
QS inhibitors (QSIs) as antipathogens Bioetchnological applications of QSIs Field trials of QSIs in treating plants, water and humans