- Email: [email protected]
Metal nanobullets for multidrug resistant bacteria and biofilms
Metal nanobullets for multidrug resistant bacteria and biofilms Ching-Wen Chen, Chia-Yen Hsu, Syu-Ming Lai, Wei-Jhe Syu, Ting-Yi Wang, Ping-Shan Lai PII: DOI: Reference:
S0169-409X(14)00170-7 doi: 10.1016/j.addr.2014.08.004 ADR 12645
To appear in:
Advanced Drug Delivery Reviews
Received date: Revised date: Accepted date:
30 November 2013 27 June 2014 11 August 2014
Please cite this article as: Ching-Wen Chen, Chia-Yen Hsu, Syu-Ming Lai, Wei-Jhe Syu, Ting-Yi Wang, Ping-Shan Lai, Metal nanobullets for multidrug resistant bacteria and biofilms, Advanced Drug Delivery Reviews (2014), doi: 10.1016/j.addr.2014.08.004
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
Metal nanobullets for multidrug resistant bacteria and biofilms
†
SC R
Ping-Shan Lai†*
IP
T
Ching-Wen Chen†, Chia-Yen Hsu†, Syu-Ming Lai†, Wei-Jhe Syu †, Ting-Yi Wang †, and
Department of Chemistry, National Chung Hsing University, 250, Kuo Kuang
NU
Rd., Taichung 402, Taiwan
MA
*Address correspondence to: [email protected]
AC
CE P
TE
D
This review is part of the Advanced Drug Delivery Reviews theme issue on “Emergence of multidrug resistance bacteria: Important role of macromolecules as a new drug targeting microbial membranes”.
1
ACCEPTED MANUSCRIPT ABSTRACT Infectious disease was one of the major causes of mortality until now because
T
drug-resistant bacteria have arisen under broadly use and abuse of antibacterial drugs.
IP
These multidrug-resistant bacteria pose a major challenge to the effective control of
SC R
bacterial infections and this threat has prompted the development of alternative strategies to treat bacterial diseases. Recently, use of metallic nanoparticles (NPs) as antibacterial agents is one of the promising strategies against bacterial drug resistance.
NU
This review first describes mechanisms of bacterial drug resistance and then focuses
MA
on the properties and applications of metallic NPs as antibiotic agents to deal with antibiotic-sensitive and -resistant bacteria. We also provide an overview of metallic
D
NPs as bactericidal agents combating antibiotic-resistant bacteria and their potential in
AC
CE P
TE
vivo toxicology for further drug development.
Abbreviation of bacteria: A.baumannii: Acinetobacter baumannii, B. cepacia: Burkholderia cepacia, B. cereus: Bacillus cereus, C. difficile: Clostridium difficile, C. jejuni: Campylobacter jejuni, C. metallidurans: Cupriavidus metallidurans, E. aerogenes: Enterobacter aerogenes, E. agglomerans: Enterobacter agglomerans, E. amnigenus: Enterobacter amnigenus, E. cloacae: Enterobacter cloacae, E. coli: Escherichia coli, E. faecalis: Enterococcus faecalis, K. mobilis: Klebsiella mobilis, K. pneumonia: Klebsiella pneumonia, K. oxytoca: Klebsiella oxytoca, S. aureus: Staphylococcus aureus,
S. enterica: Salmonella enterica, S. epidermidis: Staphylococcus epidermidis, S.
oneidensis: Shewanella oneidensis, S. typhimurium: Salmonella TyphimuriumT, S. typhus: Scrub typhus , S. Marcescens: Serratia marcescens, S. mutans: Streptococcus mutans, S. pyogenes: Streptococcus
pyogenes,
MRSA:
methicillin-resistant
S.
aureus
(Methicillin-resistant
Staphylococcus aureus), N. meningitides: Neisseria Meningitidis, P. aeruginosa: Pseudomonas aeruginosa, P. vulgaris : Proteus vulgaris, PDRAB: pan-drug-resistant A. baumannii, VRE: Vancomycin-resistant Enterococcus, V. cholera: Vibrio cholera 2
ACCEPTED MANUSCRIPT Content 1. Introduction-----------------------------------------------------------------------------------0
T
2. Mechanisms of multidrug resistance in bacteria and biofilm formation---------0
IP
2.1 Inherent (natural) resistance ---------------------------------------------------------0
SC R
2.2 Acquired resistance---------------------------------------------------------------------0 2.3 Biofilm infections and formation----------------------------------------------------0 3.
Antimicrobial
activities
of
metal
nanoparticles
against
antibiotic
NU
resistance-----------------------------------------------------------------------------------------0
MA
3.1 Gold based nanoparticles--------------------------------------------------------------0 3.2 Silver based nanoparticles-------------------------------------------------------------0
D
3.3 Copper based nanoparticles----------------------------------------------------------0
TE
3.4 Titanium based nanoparticles--------------------------------------------------------0 3.5 Zinc oxide nanoparticles---------------------------------------------------------------0
CE P
3.6 Magnesium based nanoparticles----------------------------------------------------- 0 3.7 Aluminum based nanoparticles------------------------------------------------------ 0
AC
4. Discussion and future aspects-------------------------------------------------------------0 5. References-------------------------------------------------------------------------------------0
3
ACCEPTED MANUSCRIPT 1. Introduction Infectious disease was one of the major causes of mortality in the nineteenth
T
century. Antibiotics, which were discovered in the middle of the nineteenth century,
IP
successfully reduced the mortality caused by infectious diseases [1, 2]. Antimicrobial
SC R
agents are divided into five major classes according to their principal mechanism of action: (1) inhibitors of cell wall synthesis (e.g., Penicillin and Vancomycin) [3, 4]; (2) inhibitors of protein synthesis (aminoglycoside) [5]; (3) inhibitors of nucleic acid
NU
synthesis (fluoroquinolones for DNA synthesis inhibition and rifampin for RNA
MA
synthesis inhibition) [6, 7]; (4) anti-metabolites (trimethoprim) [8] and (5) drugs that disrupt the structure of the bacterial membrane (polymyxins and daptomycin) [9]. The
D
broad use and abuse of antibacterial drugs has led to the emergence of multidrug
TE
resistance in bacteria, which has increased at an alarming rate and is now a serious issue for clinicians treating infectious diseases. Antimicrobial resistance is very
CE P
complex and the evolutionary processes usually occur during antibiotic therapy, leading to the emergence of heritable resistance to antibiotics. Horizontal gene
AC
transfer (HGT) through bacterial conjugation, transduction, transformation or biofilm formation can spread drug resistance [10]. In fact, bacterial drug resistance has numerous negative influences upon medicine and society. Infection by drug-resistant bacteria requires the administration of high doses of antibiotics, resulting in higher drug toxicity, longer hospital stays and higher mortality [2, 11]. In the United States, antibiotic-resistant bacterial infections add $20 billion to total healthcare costs and $35 billion in costs to society [11, 12]. Thus, the effective control or elimination of drug resistance is an important goal for stopping bacterial infections [13]. Recently, metallic NPs have been reported to be versatile agents that can be used in highly sensitive diagnostic assays, thermal ablation techniques, radiotherapy and drug and gene delivery [14-16]. NPs used as drug carriers might reduce the adverse effects 4
ACCEPTED MANUSCRIPT and increase the therapeutic effects of antibiotics by improving their accumulation and pharmacokinetics. [17]. It has been also demonstrated that surface functionalized
T
metal nanoarchitectures possess antimicrobial activities and thus could be used to
IP
control infectious diseases [18, 19]. Unlike traditional organic antibacterial agents,
SC R
metal NPs have a high surface area-to-volume ratio, which enhances diffusion and imparts special mechanical, chemical, electrical, optical, magnetic, electro-optical and magneto-optical properties to the NPs, properties that are different from the bulk
NU
properties [20]. The antibacterial activity of metal NPs mainly depends on their size,
MA
stability and concentration in the growth medium. [21]. To overcome the drug resistance of bacteria, NPs reveal multifunctionalities such as improvement of
D
intracellular accumulation of antimicrobial agents [22, 23] or inhibition of biofilms
TE
formation [2, 24] with fewer adverse effects comparing to traditional antibiotics [25]. This review article consists of three parts: The first part discusses the mechanisms
CE P
of antimicrobial resistance. The second part is the discussion of metal nanoparticles as antibacterial agents against drug-sensitive and -resistant microbe. In the third part, we combating
AC
provide an overview of metallic NPs as bactericidal agents
antibiotic-resistant bacteria and their potential in vivo toxicology for further drug development.
2. Mechanisms of multidrug resistance in bacteria and biofilm formation Antibiotic misuse not only causes the potentially serious effects on human health but also induces the development of antibiotic resistance in bacteria, including the multidrug-resistant bacteria: the bacteria develop resistance to multiple antibiotics and cause life-threatening infections [26]. In addition, ubiquitous antibiotic use in animals may drive the development of drug-resistant bacteria that can be transmitted to humans [27]. For the implantation of medical devices such as artificial joints and 5
ACCEPTED MANUSCRIPT cardiac valves, bacterial adhesion on the implanted biomaterials presents a constant risk of bacterial colonization and biofilm formation [28, 29]. Bacteria use numerous
T
mechanisms of resistance to antimicrobial agents and these, for the most part, can be
SC R
IP
classified as either inherent (natural) resistance or acquired resistance [30].
2.1 Inherent (natural) resistance
Inherent (natural) resistance occurs when bacteria are intrinsically resistant to
NU
therapeutic agents. For example, bacteria that lack a transport system or target for a
MA
particular antibiotic may display drug resistance as a result. In addition, cell wall play an important resistance mechanism to reduce drug uptake, thereby preventing the
D
concentration of antibacterial agents from increasing to the toxic levels in bacteria.
TE
The wall of Gram-positive cells contains a thick layer of peptidoglycan attached to teichoic acids. Comparing to the cell wall of Gram-positive cells, Gram-negative
CE P
bacteria have complex cell wall containing thin peptidoglycan layer and outer membrane that serves as an inherent barrier to hydrophobic compounds or antibiotic
AC
penetration [31, 32], indicating less susceptibility of Gram-negative bacteria than Gram positive cells to many antibiotics.
2.2 Acquired resistance Bacteria with multidrug resistance can be transformed through the acquisition of new genetic material from other resistant organisms, a process termed horizontal gene transfer (HGT). HGT is the primary cause of bacterial antibiotic resistance, and it plays an important role in the evolution of many organisms [33-35]. Transposons in bacteria can facilitate the direct or indirect transfer and incorporation of drug resistance genes into the host’s genome or plasmids (Fig. 1). These resistance genes confer resistance to various antibiotics such as β-lactams, glycopeptides, 6
ACCEPTED MANUSCRIPT aminoglycosides, quinolones, sulfonamides, macrolides, linezolid, rifampin and tetracyclines. For example, both Gram-positive and -negative bacteria usually obtain
T
genes of tetracycline efflux pumps on plasmid or transposons, including TetA, TetB
IP
and TetK, through HGT process [36]. TetR protein can repress the expression of these
SC R
efflux genes but will be inactivated by tetracycline induction, thereby expressing the
AC
CE P
TE
D
MA
NU
tetracycline efflux pumps and causing tetracycline resistance [37] .
Fig. 1. The pathway of acquired resistance by horizontal gene transfer (HGT) in bacteria through cell-cell conjugation, viral transfer and transformation.
Multidrug resistance in bacteria can also be caused by chromosomal mutations and the regulation of resistant genes. Mechanisms of this type can be classified into 4 groups (Fig. 2). (1) Inactivation or modification of drugs. For example, bacteria may acquire genes through HGT process for specific enzymes, such as β-lactamases, that can hydrolyze the β-ring of β-lactams, thereby inactivating the killing ability of β-lactams and resulting in drug resistance [36-38]. For aminoglycosides, it has been 7
ACCEPTED MANUSCRIPT found that ACT N-acetyltransferse acetylates the amino group of aminoglycosides. APH O-phosphotransferase and ANT O-adenyltransferase can phosphorylate or hydroxyl
aminoglycoside
resistance
group gene
of
aminoglycosides,
codes
for
ACT
respectively.
T
the
N-acetyltransferse,
IP
adenylates
Some APH
SC R
O-phosphotransferase or ANT O-adenyltransferase, usually located on transposons or plasmids, can modify aminoglycoside molecules, decrease the binding affinity of aminoglycoside for the 30S ribosomal subunit and therefore reduce antibacterial
NU
activity of aminoglycoside [36, 37]. Similar resistance mechanisms involved enzyme
MA
that can chemically modify antibacterial agents, are observed to combat tetracycline, macrolides, quinolones and chloramphenicol [36, 37].
D
(2) Alteration of a target site of antibiotics. It is found that many bacteria are
TE
resistant to antibiotics through this mechanism. For example, MecA gene codes for an altered penicillin binding protein (PBP), PBP2A that present low affinity for
CE P
β-lactams, are expressed in methicillin-resistant S. aureus (MRSA), and other penicillin-resistant bacteria, resulting resistance to β-lactam antibiotics [36]. The vanA
AC
gene, conferred to glycopeptides (including vancomycin) resistance, alters the binding domain of vancomycin from D-ala-D-ala to D-ala-D-lactate in peptidoglycan precursor, thereby decreasing binding affinity of vancomycin and causing resistance [36]. Drug resistance of quinolone, macrolides, aminoglycosides, linezolid, rifampin and tetractyclines can be also referred to the alternation of antibiotic binding sites. For example, fluoroquinolone resistance in S. aureus is attributed to a mutation in the quinolone-resistance determining region (QRDR) of GrlA/GrlB (topoisomerase IV) and GyrA/GyrB (DNA gyrase), which decreases the affinity of these proteins for the drug [39-42]. Erm (erythromycin resistance methylates) gene codes for a N-methyltransferase that methylases an adenine of domain V of 23S rRNA of the 50S ribosomal subunit near the binding site of macrolides, reduce the macrolides’ binding 8
ACCEPTED MANUSCRIPT and therefore result in drug resistance [36]. Methylation of 16S rRNA of the 30S ribosomal subunit and the mutation in the rpsL gene also confer aminoglycoside
T
resistance [37]. Mutation of gene that codes for the 23S rRNA of 50S ribosomal
IP
subunit significantly reduce the binding affinity of linezolids, thereby causing
SC R
linezolid resistance [36, 37]. Rifampin binds to DNA-dependent RNA polymerase and inhibits its activity. Thus, the mutation of rpoB, which codes for β-subunit of RNA polymerase, confers resistance to rifampin [37]. For tetracycline, tetL and tetM
MA
resulting in tetracycline resistance [36].
NU
resistance gene also inhibit the binding tetracycline on 30S ribosomal subunit,
(3) Alteration of a metabolic pathway. For example, sulphonamides inhibit
D
dihydropteroate synthase in folic acid metabolism through a competitive manner with
TE
higher affinity for the enzyme than the natural substrate, p-aminobenzoic acid (PABA) [43]. PABA, an important precursor for the synthesis of folic acid and nucleic acid, is
CE P
not required in some sulfonamide-resistant bacteria to perform folic acid, thereby conferring to sulphonamides resistance [44]. Bacteria can also increase the synthesis
AC
of a competitive molecule of antibiotics to inhibit its antibacterial activity. For example, sulfonamide resistance in S. aureus or N. meningitides is enhanced by increasing the synthesis of PABA that competes with sulfonamide molecules and reduces binding of drugs on dihydropteroate synthase, thereby resulting in sulfonamide resistance [45, 46]. (4) Decreasing drug permeability or increasing the active efflux (pumping out) of drugs across the cell membrane. Efflux pumps located on the membrane are high-affinity reverse transport systems that transport antibiotics out of cells before they can reach their target sites and exert their effects on bacteria. Gram-negative bacteria P. aeruginosa have multidrug efflux pump consist of H+/drug antiporter protein in the periplasmic space and will become multidrug resistant with efflux 9
ACCEPTED MANUSCRIPT protein overexpression while a gene mutation in regulatory protein that represses gene code of those efflux protein pumps [36]. Currently, drug efflux pumps can be
T
classified into five families: the ATP-binding cassette (ABC) superfamily[47], the
IP
major facilitator superfamily (MFS) [48], the multidrug and toxic compound extrusion
SC R
(MATE) family [49], the small multidrug resistance (SMR) family [50] and the resistance-nodulation-division (RND) superfamily [51]. AcrAB/TolC is the most well understood RND efflux transporters and their expressions are repressed by acrR
NU
protein. If an acrR gene mutation occur, AcrAB/TolC is overexpressed, thereby
AC
CE P
TE
D
MA
pumping out of antibiotics and causing drug resistance of bacteria [37].
Fig. 2. Various resistant strategies of bacteria against antibacterial agents.
2.4 Biofilm formation and the mechanisms of antibiotic resistance in biofilms A bacterial biofilm is a cooperative community of unicellular organisms attached to a solid surface or encased in a hydrated matrix of polysaccharide and protein. As shown in Fig. 3, biofilms are usually formed through several steps (Fig. 3A). The 10
ACCEPTED MANUSCRIPT initial step in biofilm formation is the adherence of bacteria to a foreign body or biomaterial. The transformation from reversible to irreversible attachment is a
T
relatively rapid process, taking place within a few minutes or less [52]. Bacterial
IP
adhesion is mediated by fimbriae, pili, flagella and extracellular polymeric substance
SC R
(EPS), which form a communication bridge between bacteria and the conditioning films. The aggregation and accumulation of adherent bacteria leads to the formation of multiple cell layers as the biofilm matures. The last step is the detachment of
NU
bacteria from the biofilm into a planktonic state, which allows them to initiate a new
MA
cycle of biofilm formation [53, 54]. It has been demonstrated that gene expression in biofilm cells is different than in planktonic cells [55]. Gene regulation is dependent on
D
cell population density and is controlled by a signal molecule-driven communication
TE
system, such as the quorum sensing system [56-58]. Quorum sensing occurs in many different species and environments and is mediated by a variety of factors. For
CE P
example, Bacillus and Streptococcus produce and release virulence factors [59-61]. Biofilms can form anywhere (for example, on floor tiles or on plants), and in plants
AC
they can coexist with the plant symbiotically or cause crop disease. Biofilms can also occur on contact lenses and biomedical implants [62]. Recently, the biofilm mode of growth has been suggested to be the key factor in chronic infections. Biofilms can act as a nidus that produces periodic planktonic showers of bacteria into the bloodstream, resulting in acute infections [63]. Singh et al. found that bacteria in biofilms show a thousand-fold increase in resistance to antibiotics and are less conspicuous to the immune system [64]. Therefore, it is difficult to eliminate biofilm bacteria with antibiotics in the clinic. The hypothesis of drug resistance in biofilms was reported by Stewart et al. (Fig. 3B) [65]. (1) In biofilms, the penetration of antibiotics is slow and incomplete. To kill bacteria efficiently, an antibacterial agent must diffuse and penetrate into the bacterial 11
ACCEPTED MANUSCRIPT cells. Unfortunately, EPSs affect the diffusion of antimicrobial molecules either by chemically reacting with antibiotics or by limiting their rate of transport. Hoyle and
T
co-workers reported that dispersed P. aeruginosa were 15 times more susceptible to
IP
tobramycin than intact biofilms [66]. Gilbert et al. demonstrated that the susceptibility
SC R
of S. epidermidis to tobramycin could be decreased by biofilm formation [67]. (2) A concentration gradient of a metabolic substrate or product leads to zones of slow-growing or non-growing bacteria with less uptake of antimicrobial agents than in
NU
planktonic cells. Evans and co-workers reported that E. coli grew slowly in biofilms
MA
that were resistant to cetrimide [68]. Anwar et al. reported that older chemostat-grown P. aeruginosa biofilms were more resistant to tobramycin and piperacillin than
D
younger biofilms [69]. (3) An adaptive stress response is expressed by some bacteria.
TE
To cope with environmental fluctuations, such as temperature change, oxidative stress or DNA damage, bacteria have evolved stress responses that allow adaptation [70, 71].
CE P
Many stress responses have been studied in molecular and genetic detail in planktonic bacteria, and protective stress responses may be deployed in biofilms. Junter et al.
AC
found that agar-entrapped E. coli displayed enhanced resistance to aminoglycoside because oxygen tensions were decreased. It has been suggested that the resistance of sessile-like bacteria to aminoglycoside arises from the low uptake of antibiotics by oxygen-deprived bacteria [72]. (4) A small fraction of bacteria differentiate into a highly protected persister state that reduces the susceptibility of their biofilm to antibiotics. The persister hypothesis could explain the protection of biofilms from antimicrobial agents of very different chemistries and modes of action [73].
12
AC
CE P
TE
D
MA
NU
SC R
IP
T
ACCEPTED MANUSCRIPT
Fig. 3. The schematic of biofilm life cycle and the hypothesis of antibiotic resistant mechanism in biofilms. (A) Schematic of biofilm life cycle: (1-2) Planktonic encounter a submerged surface and attached. (3-4) The slimy extracellular polymeric substance (EPS) was produced and anchors the cells to the surface. This state is commonly referred to as irreversible attachment. (5) Once attached at the surface, cell division and recruitment of planktonic bacteria results in growth and development of the biofilm community, i.e. maturation. (6) Biofilms propagated by a type of 13
ACCEPTED MANUSCRIPT "dispersal" that releases individual cells. (B) The hypothesis of biofilm resistance
T
mechanisms.
IP
3. Antimicrobial activities of metal nanoparticles against antibiotic resistance
SC R
Multidrug resistance in bacteria leads to severe consequences in patients, such as prolonged illness and a high risk of mortality. Recently, metallic nanoparticles have been investigated as potential antibiotics that could overcome resistance. The
NU
antimicrobial activities of nanoparticles are known to be a function of the their large
MA
surface area in contact with the microorganisms, particle size, and stability, as well as the drug concentration [74-78] The potential antibiotic applications of metal NPs,
D
such as gold NPs, silver NPs, magnesium oxide NPs, copper oxide NPs, aluminum
TE
NPs, titanium dioxide NPs and zinc oxide NPs, are described below.
CE P
3.1 Gold-based nanoparticles
In the 1920s, Robert Koch observed the bacteriostatic effects of gold cyanide and
AC
used it for tubercle bacillus therapy [79]. Gold compounds are clinically used to treat many diseases, including rheumatic diseases, juvenile arthritis, palindromic rheumatism and discoid lupus erythematosus [80]. Gold NPs can reveal strong light absorption in the visible region due to the coherent oscillations of the free electrons on the particle surfaces. This phenomenon of surface plasmon resonance (SPR) in gold NPs currently has various applications [81]. For example, SPR excited optically by the attenuated total reflection can be used as biosensors [82, 83]. In addition, gold NPs with coherent oscillations boundary conditions and interband electronic transitions (d to sp) [84] exhibit optical properties and photothermal effect for destructing cells or tissues [85]. Although gold NPs alone are considered that lack antibacterial activity; however, 14
ACCEPTED MANUSCRIPT Dakshinamurthy et al. synthesized dextrose-encapsulated gold nanoparticle (dGNPs) with average diameters of 25 nm, 60 nm and 120 nm (± 5), and they found that the
T
120-nm dGNPs were the most potent antibacterial agents through disruption of
IP
bacterial cell membrane against both Gram-negative (E. coli) as well as
SC R
Gram-positive (S. epidermidis) bacteria [86]. Gold NPs can be synthesized to give them chemical or photothermal functionality; for example, they can be made into nanospheres, nanocages or nanorods with near-infrared (NIR) absorption that can
NU
destroy cancer cells and bacteria via photothermal heating [87, 88]. For example,
MA
anti-salmonella-antibody-conjugated oval-shaped gold NPs can kill S. typhimurium after NIR radiation via photothermal lysis [89]. Gold NPs can also be combined with
D
antibiotics to enhance antibacterial efficiency. Gold NPs coated with aminoglycosidic
TE
antibiotics have antibacterial effects on a range of Gram-positive and Gram-negative bacteria [90]. The antibacterial activity of gentamicin significantly increases when it
CE P
is mixed with gold nanoparticles [91]. In addition, chitosan-capped gold NPs coupled with ampicillin show twice as much antibacterial activity as free ampicillin against E.
AC
coli, S. aureus and K. mobilis [92]. Recently, the combination of photothermal gold nanoparticles with antibodies or antibiotics was shown to produce synergistic effects for antibacterial activity. Gold NPs conjugated with anti-protein A antibodies that photothermally kill S. aureus after laser irradiation [93]. Sabo-Atwood et al. conjugated polyclonal antibody against P. aeruginosa isolate (PA3) on the surface of gold nanorods and demonstrated that antibody-conjugated nanorods effectively kill pathogenic P. aeruginosa via photothermal cell lysis [94]. Vancomycin-bound gold NPs also showed successful hyperthermic killing of pathogens including Gram-positive (S. pyogenes and S. aureus), Gram-negative (E. coli UTI (urinary tract infections), E. coli O157:H7, A. baumannii) and antibiotic-resistant bacteria (Vancomycin-resistant Enterococcus 15
ACCEPTED MANUSCRIPT (VRE), methicillin-resistant S. aureus (MRSA) and pan-drug-resistant A. baumannii (PDRAB)) via NIR irradiation [95].
T
The surfaces of gold NPs are easily modified for different types of antibacterial
IP
treatments. It has been reported that photosensitizers conjugated with gold nanorods
photo-hyperthermia
[88].
Gold
nanorods
SC R
killed MRSA by photodynamic antimicrobial chemotherapy (PACT) and NIR conjugated
with
a
hydrophilic
photosensitizer, toluidine blue O, were used for antimicrobial photodynamic therapy
NU
and hyperthermia via synergistic combination effects to kill MRSA [96]. The
MA
antimicrobial activity of the antibiotic vancomycin against vancomycin-resistant enterococci (VRE) was enhanced by coating with gold NPs [97]. Ampicillin-capped
D
gold NPs also show potential antibacterial activity against multidrug resistant bacteria,
TE
including MRSA, P. aeruginosa, E. aerogenes and E. coli K-12 substrain DH5-alpha [98].
CE P
The detailed mechanisms that allow gold NPs to inhibit bacterial growth are still under investigation. Cui et al. found that the antibacterial action of gold NPs depends
AC
on two events: decreasing the intracellular ATP levels by alternation of membrane potential or inhibition of ATP synthase activity and inhibition of the tRNA-binding subunit of the ribosome. The action of gold NPs does not include a reactive oxygen species (ROS) mechanism, although ROS damage is the cause of cellular death induced by some bactericidal antibiotics and nanomaterials [99]. Liang et al. demonstrated that gold NPs with different surface modifications but the same shape and particle size exhibited different inhibitory effects. Poly-allylamine hydrochloride (PAH)-capped gold NPs caused cell lysis, whereas citrate-capped gold NPs did not [100]. Gold NPs coated with a second generation β-lactam antibiotic, Cefaclor, have efficient antimicrobial activity on both Gram-positive (S. aureus) and Gram-negative bacteria (E. coli), in contrast to Cefacior or gold NPs treatment alone [18]. When used 16
ACCEPTED MANUSCRIPT against Gram-positive bacteria, cefaclor first reacted with the outer peptidoglycan layer and increased the membrane porosity. Subsequently, gold NPs penetrated into
T
the bacteria and prevented DNA from unwinding, stopping transcription. This
IP
phenomenon provided the antibacterial activity of the cefaclor-capped gold NPs.
SC R
When used against Gram-negative bacteria, gold NPs first penetrate through the membrane, and cefaclor reacts with the inner peptidoglycan layer, generating holes in the membrane. The DNA binding of gold NPs subsequently occurs, resulting in
NU
slower antibacterial activity compared to the fast activity observed in Gram-negative
MA
bacteria [18, 90].
D
Silver-based nanoparticles
TE
Silver ions and silver-based compounds are highly toxic to microorganisms [101-103], and they have been widely used for biomedical applications such as the
CE P
treatment of burns, wounds and infections [104-106]. In general, silver is applied in its nitrate form to induce an antimicrobial effect. Recently, nanosized silver particles
AC
with greatly expanded surface areas were shown to have excellent antimicrobial properties [107, 108], and such particles can now be used as disinfect filters and coating materials against bacteria [109, 110]. Mecking et al. showed that hybrids of silver NPs with amphiphilic hyperbranched macromolecules showed effective antimicrobial properties when used as surface-coating agents [111]. For wound healing, silver NPs provide antibacterial ability that significantly reduces scar formation in a dose-dependent manner by decreasing inflammation through cytokine modulation [112]. Recently, silver NPs and coatings of other silver species have been used on implants and medical devices to impede the formation of biofilms and decrease the incidence of infections [113, 114]. Silver NPs also have antibacterial activity against a 17
ACCEPTED MANUSCRIPT wide of bacteria including drug resistant microbes. A study by Lara et al. showed the potential bactericidal silver NPs against multidrug resistant P. aeruginosa,
T
ampicillin-resistant E. coli O157:H7 and erythromycin-resistant S. pyogenes [115].
IP
Dolman et al. also showed that the silver-containing Hydrofiber® dressing and
SC R
nanocrystalline silver-containing dressing are effective agents against Gram-negative bacteria, including P. aeruginosa, K. pneumonia and E. coli; Gram-positive bacteria, including E. faecalis, S. aureus and antibiotic resistant bacteria, such as MRSA, VRE
NU
and S. Marcescens. These dressings on biomaterials also work by preventing biofilm
MA
formation [116]. It is also shown that silver NPs can act not only as antibacterial agents but also as antiviral and antifungal agents [117, 118]. Silver NPs immobilized
D
on the surface of nanoscale silicate platelets (AgNP/NSPs) also have strong
TE
antibacterial activity against MRSA and silver-resistant E. coli. These particles exert their effect through the generation of ROS at the contact surfaces [119]. Therefore,
CE P
nanoscale silver crystals can act as effective broad spectrum bactericidal agents against both drug-sensitive and -resistant microbes.
AC
Silver NPs have great antibacterial activity through multiple mechanisms. Morones et al. suggested that silver NPs first attach to the surface of the cell membrane, disturb its function, penetrate the bacterium and release silver ions that result in efficient antibacterial activity against Gram-negative bacteria (E. coli, V. cholera, P. aeruginosa and S. typhus) [120]. Salopek-Sondi and Dash demonstrated that silver NPs can anchor to the bacterial cell wall, penetrate the cell wall and finally lead to cell death [121, 122]. It is noted that silver NPs with smaller volume and larger surface area have increased ability to penetrate through the cell wall and cell membranes into bacterial cells [123]. The generation of free radicals by silver NPs is also considered to be a possible mechanism of antibacterial activity. Kim et al. reported that free radicals produced by silver NPs can cause cell membrane damage and increase 18
ACCEPTED MANUSCRIPT membrane porosity, leading to cell death [124]. Intracellular silver ions released from silver NPs can interact with phosphorus moieties in DNA to inactivate DNA
T
replication. Silver ions can also react with sulfur-containing proteins to increase the
IP
ROS level and inhibit respiratory enzymes, resulting in cell death [120, 125, 126]. The
SC R
hypothesis is that silver ions act as soft acids to facilitate the formation of complexes with sulfur- or phosphorus-containing ligands, which act as soft bases [120, 127]. Chueh et al. showed that the action of silver NPs evokes inflammatory responses in
NU
host cells due to ROS production, which induces cell apoptosis and increases the
MA
transcription of pro-inflammatory cytokines via activation of the c-Jun N-terminal
D
kinase pathway [128].
TE
Copper-based nanoparticles
Copper, one of the essential trace elements, is vital to organisms and crucial for the
CE P
functioning of organs and metabolic processes; however, in low or excessive amounts, copper can have deleterious effects [129-131]. It is demonstrated that copper can act
AC
as an electron donor/acceptor by alternating between the redox states copper (I) and copper (II) in some enzymes, thereby increasing toxicity to the bacteria [132, 133]. An alternative route of copper ion induced toxicity is proposed to involve the displacement of iron from iron-sulfur clusters [134]. However, some bacteria such as C. difficile may protect themselves from the toxic effects of copper or copper ions while contacting with copper surface. One of possible mechanisms regarding copper resistance of bacteria is due to the formation of endospores [135]. The antibacterial abilities of copper have been widely tested in human pathogens, including MRSA, C. difficile, E. coli and P. aeruginosa [136]. A remarkable decrease in viable bacteria was observed after incubation with metallic copper; thus, the main 19
ACCEPTED MANUSCRIPT mechanism of antibacterial activity for copper is suggested to be contact-mediated killing. For example, the B. cepacia complex consists of 17 closely related bacterial
T
species that are difficult to eradicate, and it was observed that the contact time of
IP
copper on the B. cepacia complex is an important factor for antibacterial activity [133,
SC R
137]. A study of Faudez et al. also showed similar results for S. enterica and C. jejuni [138]. The contact interface is also important for copper-mediated antibacterial activity. In a “dry” test, a very small amount of liquid is dropped on the metallic
NU
surface with a cotton swab. It evaporates within seconds, thereby allowing direct cell
MA
contact with the metal [131, 139]. The minimal required time for complete B. seminalis death was 1 minute on dry copper surfaces, but it was 14 hours on moist
D
copper surfaces [137]. The color change of copper from dark brown to pale blue via
TE
oxidation-reduction reactions can be used as a simple indicator for copper (II) ion release in a copper contact assay [138].
CE P
By the paper disc assay, copper powder has been shown to be an efficient antibacterial agent against drug-resistant Enterobacter species [140]. Noyce et al. investigated copper’s antimicrobial effects on different strains of MRSA and reported
AC
the complete killing of 107 cfu inoculums of MRSA (NTCT 10442) on copper [141]. Steindl et al. also reported that MRSA ST398, NDM-1-producing K. pneumonia and CTX-M-producing E. coli were sensitive to copper, with less than 103 cfu remaining after 2 hours [142]. Copper also exerts strong antibacterial effects through the bacterial intracellular influx of copper ions in the B. cepacia complex [137]. Bacterial contact killing by copper is preceded by a sequence of specific actions: cell membrane damage, copper influx into the cells, oxidative damage and DNA damage [143]. The targeting of DNA by copper leads to rapid DNA fragmentation and cell death [133, 144]. After exposure to copper, fragmented or tailed DNA can be observed in the B. cepacia complex and Enterobacter [137, 145]. Copper-based NPs 20
ACCEPTED MANUSCRIPT also show potential for the direct or indirect killing of multidrug-resistant bacteria. Through the combination of other materials with copper nanoparticles, it is possible to
T
create versatile antibacterial agents that work on drug-sensitive and drug-resistant
IP
bacteria [146-150]. Strickand et al. showed that a copper-cotton nanocomposite was
SC R
efficient at killing multidrug-resistant bacteria not only by direct contact killing but also by enhancing the release of copper ions [148]. Copper NPs can be capped with a cationic polymer such as chitosan to enhance their interaction with the negatively
NU
charged cell envelope [151]. Compared to Gram-negative bacteria such as E. coli.,
MA
Gram-positive bacteria (e.g., S. aureus) are more sensitive to copper nanoparticles [74, 75, 152]. Amal et al. investigated the source of toxicity of copper oxide NPs by
D
examining their leaching characteristics and speciation, and the results showed that
TE
the rates of cellular ROS generation in E. coli are different for different sizes of NPs [149]. ROS most likely formed on the surfaces of copper NPs in the presence of
CE P
amine functional groups from various biological molecules [153]. Thus, copper-based NPs serve as potential antibacterial agents that can kill drug-resistant bacteria, and
AC
their antibacterial mechanism may need to be evaluated in greater detail.
Titanium (IV) oxide-based nanoparticles The applications and properties of titanium (IV) oxide (TiO2) have been known for over 90 years [154]. TiO2 NPs as catalyst can generate electron–hole pairs with photo-excitation, initiate cascade oxidative-reductive reactions at the TiO2 surface and therefore produce ROS for further reactions [155]. For microbial killing, TiO2 NPs with light irradiation significantly inhibit the growth of bacteria through the peroxidation of lipids in membranes, DNA damage or oxidized nucleotides, and oxidation of amino acids or breakage of protein catalytic centers via photocatalysis [156]. The self-cleaning ability of TiO2, which can be used in environmental 21
ACCEPTED MANUSCRIPT purification to remove contaminants in the air and water, is well known [157, 158]. TiO2 NPs with photocatalytic disinfection abilities can be used as antibacterial agents
T
for antibiotic-sensitive and antibiotic-resistant bacteria [155, 159-161].
IP
The structures of TiO2 can be classified into three crystalline forms: anatase, rutile
SC R
and brookite. TiO2 NPs in the anatase form show the highest photocatalytic efficiency. Recently, it was shown that a mixture of these crystalline structures (79% anatase and 21% rutile phases or brookite-anatase which consist of 45% anatase, 2% rutile, and
NU
53% brookite) also has good photocatalytic activity [162, 163]. When TiO2 NPs are
MA
irradiated with wavelengths below approximately 385 nm, the absorption of a photon with sufficient energy (equal to or higher than its band gap, ~3.2 eV) transfers
D
electrons from the valence band (O 2p) to the conduction band (Ti 3d), leaving a
TE
positively charged hole in the valence band. These electron/hole pairs can react with oxygen or water to form superoxide (O2·) or hydroxyl radicals (OH·) that has a ability
CE P
to decompose organic species into carbon dioxide and water [155]. Thus, TiO2 NPs can be applied to kill bacteria, to eliminate viruses, and even to clean up some odor
AC
molecules [164-166]. When final process of photocatalysis was completed, various highly active oxygen species had been generated. Thus, these highly active species would be reacting with organic matters such as odor molecules, bacteria and virus then causing these reactants degradation or destruction. It was reported that TiO2 NPs can kill both Gram-negative and Gram-positive bacteria by photocatalysis, although Gram-negative bacteria are particularly sensitive [167-169]. This difference between Gram-negative and Gram-positive bacteria may be due to their different cell wall structures. Gram-negative bacteria have a triple-layer cell wall structure with a thin peptidoglycan layer in the inner and outer membranes, whereas Gram-positive bacteria have only one thicker peptidoglycan layer that facilitates the absorbance of reactive radicals, thereby preventing cell damage from radical attack [169]. TiO2 NPs 22
ACCEPTED MANUSCRIPT have bactericidal effects through multiple mechanisms. Matsunaga et al. showed that the TiO2 has the potential against bacteria via receiving an electron from intracellular
T
coenzyme A (CoA) after the photocatalysis of TiO2, followed by the formation of
IP
dimeric CoA and the subsequent inhibition of respiration [170]. T. Saito et al.
SC R
demonstrated that the photochemical reaction caused by TiO2 NPs disrupted the cell membrane and the cell wall to cause cell death [171]. These membrane structure change phenomena can be observed by scanning electron microscopy or transmission
NU
electron microscopy [172, 173]. The production of aldehydes, ketones, and carboxylic
MA
acids is also considered to be evidence of membrane degradation or peroxidation in E. coli cells treated with TiO2 NPs [174]. The internal components of lysed bacteria leak
D
from the cells through the damaged area, resulting in cell death via photocatalysis
TE
[175]. Thus, TiO2 NPs with suitable irradiation provide a promising and feasible approach for the disinfection of pathogenic bacteria, thereby facilitating the
CE P
prevention of infectious diseases.
The antibacterial activity of TiO2 NPs is also dependent on particle size, light dose
AC
and the wavelength of irradiation [176]. Shah et al. showed that 10-15 nm TiO2 NPs with highly efficient membrane damage against multidrug-resistant S. aureus via efficient photocatalysis [177]. In addition, TiO2 NPs can reduce the adhesion of bacteria and inhibit the formation of biofilms [178, 179]. However, TiO2 NPs did not show good bactericidal efficiency against some types of drug-resistant bacteria (e.g., C. metallidurans CH34) that have a remarkable capacity to resist membrane damage caused by ROS via the overexpression of protective components and membrane restoration elements [180]. Thus, TiO2 NPs combined with other agents with different antibacterial mechanisms may provide a potential bactericidal strategy to use against drug-resistant bacteria. 23
ACCEPTED MANUSCRIPT Zinc oxide nanoparticles Zinc oxide NPs also show bactericidal activity via multiple mechanisms including
T
photo-oxidation and photocatalysis [181]. The antibacterial effects of zinc oxide
IP
depends on the volume of NPs. Sasamoto et al. showed zinc oxide NPs (10-50 nm)
SC R
exhibited better antimicrobial properties than bulk zinc oxide (2 μm) [182]. The cell penetration of smaller size of zinc oxide NPs can be enhanced by ultrasound. A study of Thomas et al. demonstrated that the combination of zinc oxide NPs with ultrasound
NU
enhanced the antibacterial effect on S. aureus by generating more hydrogen peroxide
MA
[152]. In addition, ultrasonic treatment can physically facilitate the dissociation of cell membranes, thereby increasing the penetration of zinc oxide NPs into cells.
D
For combating with drug resistant bacteria, zinc oxide NPs with a diameter of ~19 nm
TE
can be used against strains of Enterobacteriaceae, especially E. coli and K. pneumoniae, that exhibit extended spectrum β-lactamase (ESBL)-mediated resistance
CE P
to third-generation cephalosporins [183]. The activity of these particles may depend on disruption of the cell membrane [184] and therefore produce greater leakage of
AC
cytoplasmic contents while they are in contact with the bacteria [185]. Another antibacterial mechanism of zinc oxide NPs is the increase in intracellular ROS levels (such as OH·, H2O2, and O2-·), which is activated by UV and visible light irradiation. The OH· and O2-· cannot penetrate the cell membrane because of their charges or reactivity [186] and are likely to remain on the cell surface, whereas H2O2 can penetrate into bacterial cells, thereby inducing cell death during infection [187-189].
Magnesium-based nanoparticles Magnesium oxide NPs and magnesium halogen-containing NPs are two major magnesium-based antibacterial agents to combat microbes. Magnesium oxide NPs reveal strong interactions with negatively charged bacteria and spores because of their 24
ACCEPTED MANUSCRIPT large surface area, the abundance of crystal defects and positively charged particles [190, 191]. Active oxygen formation, such as superoxide O2-, on the surface of
T
magnesium oxide is considered to be one of antibacterial mechanisms of magnesium
IP
oxide[182, 192]. Magnesium oxide NPs exhibit activity against bacteria, spores and
SC R
viruses after adsorption of halogen molecules. These metal halogene complexes show bactericidal effects through the following possible mechanisms: formation of ROS that may cause lipid peroxidation of microbial cell envelope, alteration of membrane
NU
potential or inhibition of certain enzymes of bacteria [193], MgF2 NPs that can inhibit
MA
growth and biofilm formation of E. coli and S. aureus is a typical of magnesium
D
halogene complexes[193].
TE
Aluminum-based nanoparticles
Aluminum-based nanoparticles are thermodynamically stable across a wide range
CE P
of temperatures, and they are easy to protect while aluminum is exposed and in contact with atmospheric oxygen. A self-passivating oxide layer of alumina forms on
AC
the particles rapidly, which provides a protective covering that stops further oxidation [194]. Aggregations of particles are affected by pH and salinity, variations of which may lead to different toxicity assessments. At near-neutral pH, the prepared alumina NPs have a positive surface charge that improves the electrostatic interactions between the negatively charged surface of E. coli cells and the alumina particles, resulting in the adhesion of alumina NPs on the surfaces of the bacteria [195, 196]. The common antimicrobial effects of metal-based NPs work through ROS generation, which disrupts cell walls and leads to cell death. Interestingly, alumina NPs may serve as radical scavengers [197]. Mukherjee reported that alumina NPs mildly inhibited E. coli at high concentrations of up to 1,000 μg/mL, and they showed that this can cause distortion in bacterial cells [198, 199]. However, aluminum oxide NPs might actually 25
ACCEPTED MANUSCRIPT increase the likelihood of developing drug resistance. Qiu et al. demonstrated that aluminum oxide NP increases the risk of horizontal transfer of antibiotic resistance
T
genes by up to 200 times (in the case of transfer from E. coli to Salmonella by
IP
conjugation) [200]. The oxidative damage caused by aluminum oxide NPs may
SC R
trigger an increase in gene expression to promote conjugation.
Discussion and future directions
NU
In the past few decades, multidrug resistance has emerged in many frequently
MA
encountered pathogenic bacteria, sometimes culminating in resistance to all licensed antibacterial agents [13]. Thus, the emergence of antibiotic- resistant bacteria is
D
recognized as a crucial challenge facing public health. NPs offer a new strategy for
TE
killing drug resistant bacteria. To combat the resistant bacteria, NPs can efficiently administer antibiotics by improving their accumulation and pharmacokinetics and
CE P
reducing their adverse effects [17]. In addition, metallic NPs as antibacterial agents provide several advantages in treatment of the drug resistant bacteria. First, NPs with
AC
high surface area to volume ratio not only reveal new mechanical, chemical, electrical, optical, magnetic, electro-optical, and magneto-optical properties against bacteria [20] but also attack a broad range of targets in the bacteria, thereby increasing antimicrobial efficacy in drug sensitive or resistant bacteria. Second, metallic NPs act as versatile antibacterial agents that can significantly reduce the risk of metallic NPs-mediated bacterial resistance compared with classic antibiotics-induced resistance [201, 202]. Table 1 summarizes recently published work on antibacterial treatments using metallic and metal oxide NPs against drug-resistant bacteria and biofilm formation. Several metallic NPs, such as superparamagnetic iron oxide (SPIO)-based NPs, Bi-NPs, CaO-NPs, W-NPs that show antibacterial abilities are also included [203-207]. Most metallic NPs reveal antibacterial activity through multiple 26
ACCEPTED MANUSCRIPT mechanisms that can be explained why metal based NPs can combat drug-resistant bacteria, including the inhibition of biofilm formation (Fig. 4). Attachment of metallic
T
NPs on cell surface first cause cell membrane damage or permeability change, thereby
IP
enhancing penetration of NPs into bacterial cells. Metallic NPs with external
SC R
stimulation, such as UV, visible or NIR light irradiation, facilitate penetration of particles. Intracellular ROS generation or metal ion release from metallic NPs usually cause the damage of biomolecules (enzyme, DNA, ribosomal subunit, mRNA),
NU
thereby inactivating its functions and enhancing cell death. Blocking of efflux pump is
MA
also a specific mechanism of metallic NPs against drug resistant bacteria. Here we show many literatures regarding metallic NPs against bacteria; however, some
D
bacteria may defense themselves against metallic NPs. For example, S. oneidensis
TE
MR-1 (-) has excellent resistant against copper ion released from copper-doped TiO2 because this strain produce EPSs under NP stress [208]. Thus, package of multiple
CE P
antibacterial agents in one metallic nanoparticle might a potential nanobullet against multiple drug resistance of microbes.
AC
However, there are still several disadvantages of metallic NPs as antibacterial agents. The major one is the potential nanotoxicity of metallic NPs after administration. To facilitate the use of metallic NPs as antibacterial agents for human health, the toxicity of NP exposure in animals and humans must be studied before large-scale production [209]. Table 2 summarizes the in vivo toxicity of metal NPs. The toxicities of NPs are affected by three factors: (1) the solubility, charge and shape of the NPs causes different levels of toxicity in animals [210]. (2) The modification of NPs or their surfaces can also alter their toxicity. For example, morphological changes of nanomaterials may cause them to be unrecognizable to phagocytic cells, lead to more toxicity [211]. (3) The size of NPs also influences their toxicity. Small NPs that show efficient antibacterial activity may easily penetrate the skin, lungs, and brain and 27
ACCEPTED MANUSCRIPT cause adverse effects. In addition, metallic NPs, after administration, might be accumulated mainly in the organs, including the spleen, liver and kidney, which may
T
result in different degrees of injury [212]. Frangioni et al. proposed three criteria for
IP
distinguishing a nanoparticle have a clinical potential candidate: (1) a final
SC R
hydrodynamic size≦5.5 nm to permit complete elimination from the body and/or (2) the formulation without toxic components and/or (3) the formulation compositions have the ability of biodegrading into clearable components [213]. Thus, the metallic
NU
NPs and their formulations need to satisfy these criteria to push them into clinical trial.
MA
Moreover, the potential harmful and toxicities of metallic NPs have to be studied via systemic and consistency assessment methods. The experimental platforms based on
D
metallic NPs and biological species are difficult to generalize in individual studies.
TE
Thus, the correlation between physicochemical properties of metallic NPs and bacteria killing ability or nanotoxicology is not easy to be clearly defined [214]. To
CE P
unravel systematically nanotoxicology of NPs, nanotoxicological community has discussed the general guidelines and established common parameters regarding
AC
nanotoxicology for further nano-related studies that can efficiently accelerate the using of nanoproducts for clinical applications [215].”
28
AC
CE P
TE D
MA N
US
CR
IP
T
ACCEPTED MANUSCRIPT
Fig. 4. Multiple mechanisms of metallic NPs against drug-resistant bacteria
29
ACCEPTED MANUSCRIPT
Table 1. Various metallic NPs against pathogenic bacteria and their formation of biofilm metallic NPs
properties of metal NPs
potential of metallic NPs
Au-PAA-TBO nanorod
Toluidine blue O (TBO) conjugation
Au nanorods: length: 35 nm, width: 9.3 nm
Bacteria
Antibiotic resistance type
S. aureus (+)
US MA N
(HR-TEM)
TE D
n–Au-NPs
CE P
1.8–2.0 nm
AC
conjugate
IgG-conjugated anti-PA3 primary Au nanorods antibodies conjugation
Au nanorods: length: 68 nm, width: 18 nm
P. aerugnosa (-)
Mechanisms of
Remarks
Refs
antibacterial action
Gold based NPs Methicillin-resistant
(TEM), ~13 mV
TBO –tioproni
Applied dosage
T
Size and zeta
0.9-1.8×109 Au nanorods, 633 nm laser for 1 min
Photodynamic inactivation and hyperthermia
Combination of PACT and hyperthermia
(PACT) and 808 nm laser for 25 min (hyperthermia)
effect
TBO(4
Photodynamic
led to an enhanced antimicrobial effect (~32 % additive effect) Increased
μM)–tiopronin–Au-N Ps: ~18.4 μg/mL, PDT: 632.8 nm laser, 2.1-10.5 J
inactivation, killing bacteria in light dose dependent manner
IP
Surface physical
CR
Composition of
[88]
[96]
extinction coefficient of the conjugate compare to free TBO result in
four-folds reduction in MBC Cipromycin, Au nanorod: Antibody Covalently [94] imipenem, unrevealed, NIR recognition, NIR coupled and gentamicin- light: 785 nm, 80 treatment result in antibody-nano 30
ACCEPTED resistantMANUSCRIPT mW, 5 minutes
(TEM)
irreparable bacterial
rod complex cell is much more
nm P. aeruginosa (-)
Biofilm formation
IP
100–300 (DLS)
CR
Au-NPs–polyth Polythiophene iophene (PTh) blended
stable under physiological conditions Au-NPs-PTh: 30-112 Au-NPs-PTh Without [216] μM (antibiofilm could pervade cytotoxicity activity assay) through the on HT-29 extracellular cells even at
T
surface damage
US
composite
TE D
MA N
matrix and then an access to the Au-NPs-PTh structured of of 112 μM bacteria microcolonies embedded in the
Ag-NPs
Bare silver
10–15 nm (TEM), weak
AC
CE P
biofilm result in cellular membrane damage
E. coli (-)
Silver based NPs Ampicillin- resistant
positive charges S. typhus (-)
Multi-drug resistant
31
Ag-NPs: 5-25 μg/mL (agar diffusion
Anchor to the cell Dose membrane, dependent,
method)
perforations formation in the membrane result in cell lysis
gram-negative bacteria are more susceptible, black debris was observed
[217]
ACCEPTED MANUSCRIPT
which was proposed a
CR
IP
T
defense mechanism to deplete locally Ag concentration Best [218] antimicrobial
DLS results: Glucose:
S. epidermidis Methicillin-resistant (+)
saccharides as reducing agent)
~44-453 nm
S. aureus (+)
Lactose:
Vancomycin-resistant
evaluated respectively, Ag: 0.84-54 μg/mL (MIC and MBC assay)
K. pneumoniae ESBLs (-)
AC
CE P
~35-286 nm
E. faecium (+)
MA N
Maltose: ~25-290 nm
Smallest Ag Proposed colloid-NPs size were mechanism:
TE D
Galactose: ~50-343 nm
US
Ag colloid-NPs Not shown (various
Biosynthetic Ag-NPs
Not shown
10-20 nm (TEM), 15 nm (XRD)
E. coli (-), P. Multi-drug resistant aeruginos (-) and S. aureus (+)
32
Ag-NPs: 50 ppm (disc diffusion method)
attach to the cell membrane, disturb its permeability and respiration, penetrate into the
effect: 25 nm-size (maltose), Lowest antimicrobial effect: 50
bacteria, Agcolloid-NPs and its releasing silver ions react with bacterial DNA
nm-size (galactose) and self-aggregati on was observed in hours
Ag-NPs attach onto surface bacteria membrane disturbing
may the of cell
Biosynthesis [219] of Ag-NPs from B. thuringiensis spore crystal the mixture
ACCEPTED MANUSCRIPT
160-180 nm (AFM)
S. aureus (+) Methicillin-resistant and S. epidermidis (+)
Ag-NPs: 2 μg in 20 μL (well diffusion method)
T
Not shown
function Citing reference: inhibition of bacterial cell wall synthesis (MRSA)
Amino acid 550–650 nm residues and (AFM) protein which are present in the
Ag-NPs: 5-15 μL (disc and well diffusion method)
Unrevealed
AC
CE P
bio-synthesis procedure
S. aureus (+) Methicillin-resistant and S. epidermidis (+)
TE D
Biosynthetic Ag-NPs
MA N
US
CR
IP
Biosynthetic Ag-NPs
permeability and respiration
Ag–NPs immobilized in alginate beads (Ag–Alg biohydrogel)
Not shown
< 15 nm in the
S. aureus (+),
Erythromycin-
polymer (TEM), 4.9 nm (XRD)
B. cereus (+), E. resistant faecalis (+), E. coli (-), P. aeruginosa (-), K. pneumonia (-), and S. 33
Ag–Alg biohydrogel:
Cell surface
2 mg (agar diffusion method)
damage and lost of the chain integrity
Biosynthesis [220] of Ag-NPs from S. aureus, Gram-positive bacteria were susceptible to Ag-NPs Biosynthesis [221] of Ag-NPs from A. clavatus, non zone of inhibition for both MRSA and MRSE in 5 μL of Ag-NPs Biosynthesis [222] of Ag-NPs from actinobacteria Rhodococcus NCIM 2891, which was
ACCEPTED MANUSCRIPT typhimurium (-)
immobilized in alginate,
Tehran Company)
E. coli (-), A. 186 clinical samples baumannii (-), S. marcescens (-), E. cloacae (-), K. oxytoca (-), E. aerogenes, C.
membrane, cell membrane destruction, removal of intracellular materials and causing bacteria
(Wistar rat) was observed on 3 days after intraperitoneal injection (50 ppm) but liver
freundii (-) and P. vulgaris (-)
death
damage returned on 8 days after the injection Reduction in [224] bacterial
CE P
TE D
K. pneumoniae ESBLs producing (-), P. microorganisms aeroginosa, (-), which isolated from
Pars
Ag-NPs: 12.5-500 ppm (disc diffusion method)
Commercial Ag-NPs
Gram negative bacteria Citing reference: Severe [223] Ag-NPs penetrate irritation in into bacterial cell liver cells
Not shown 4 nm (purchased from Nano Nasb
AC
Commercial Ag-NPs
MA N
US
CR
IP
T
Gram positive bacteria were found to have some resistance to Ag-NPs more than that of
Not shown (procured
5-10 nm
S. aureus (+)
Methicillin-resistant
from 34
Ag-NPs: ~1.56-200 μg/mL, MIC: 12.5
Unrevealed
ACCEPTED MANUSCRIPT μg/mL, MBC: 25
Nanoparticle Biochem, Inc.)
μg/mL
Methicillin-resistant
E. coli (-)
Ampicillin-resistant
Ag-NPs: 30-100 mM (MIC and MBC assay)
IP
T
S. aureus (+)
CR
Not shown 100 nm (Sigma–Aldrich Co., LLC.)
Multi-drug resistant
Ag-NPs concentration Suggested Ag-NPs mechanism: resistant destabilizing and strains were disrupting the grown at outer membrane, various denaturing the 30s ribosome subunit, suppressing ATP production, inhibiting
Ag-NPs concentration: MRSA (100 mM), drug-suscepti ble S. aureus
respiratory enzymes, binding and dimerizing RNA and DNA
(200 mM), multi-drug resistant P. aeruginosa (75 mM), ampicillin-resi stant E. coli
AC
CE P
TE D
P. aeruginosa (-)
MA N
US
Commercial Ag-NPs
growth with increasing
Poly(acrylami de/itaconic acid)-Ag-NPs (P(AAm/IA)Ag-NPs)
Bare silver binding with nitrogen and oxygen moieties of copolymer
42.11-50.6 nm (20-70 kGy gamma irradiation, XRD)
S. aureus (+)
Methicillin-resistant
P(AAm/IA)-Ag-NP s: 5-200 μg/mL (MIC and MBC assay)
35
Attached to the surface of bacterial cell wall, permeated the cell
[225]
(75 mM) Polymerizatio [226] n of monomer by gamma irradiation, multi-drug
membrane and entered into the
resistant P. aeruginosa
aeruginosa (-)
cell interior, cell membrane damage result in changing the cell permeability, leak the intracellular contents by cell
was most susceptible to
Predominantly P. aeruginosa two sizes of (-) and S. CS-Ag-NPs: 55 aureus (+) and 278 nm (DLS), 51.1 mV
Biofilm formation
MA N
Chitosan coating
TE D
Chitosan coated Ag-NPs
US
CR
IP
T
ACCEPTED MANUSCRIPT K. pneumoniae Multi-drug resistant (-), and P.
CE P
cause by the interaction of silver ions with phosphorous- and sulfur-containing compounds
AC Ag-based-NPs coated carboxymethyl ated cotton
Bare metal or Not shown metallic oxide
A. Baumannii(-)
0.5-5 ppm (antibiofilm activity assay)
disruption Cell integrity destruction, DNA fragmentation, irreversible damage may
Multi-drug resistant
36
~12 μg Ag in bacteria Contact-killing liquid culture mechanism (high surface area to volume ratio)
P(AAm/IA)Ag-NPs
Cytotoxicity in macrophages was not significantly
[227]
affected in the presence of 3 ppm but dropped drastically at the nanoparticle concentration of 10 ppm Proved to be fatal to NIH3T3 cell
[148]
Ag-NPs/NSP
Bare silver which immobilized on the surface NSP
of
ANP-NPs: 6.66±2.7nm (TEM),
MANUSCRIPT S. aureusACCEPTED (+) Meticillin-resistant Ag-NPs/NSP: 64.9 Conducted in E. μM, 129.8 μM, 324.5 coil: the
NSP
average
US
CR
IP
T
dimension of 80×80×1~100× 100×1 nm3
μM and 648.9 μM conentation of (MIC assay) Ag-NPs on the NSP is predominant factor on biocidal effect, bacteria cell membrane
MA N S. aureus (+)
methicillin-resistant
N-alkylation of poly(4-vinylpyr idine)
0.4-20 mg composite in 0.5 mL of mammalian fluid (serum, saliva, or blood)
37
[119]
activity of Ag-NPs/NSP on silver-resistan t E.coli by bypassing Ag+ mechanism
surfaces adhesion, integrity of the inner membrane breakage, ROS generation, nutrient uptake
TE D TEM results: AgBr/NPVP: Ag/Br ratio in compostie/%
CE P
NPVP blended
AC
AgBr-NPs/NP VP composite
The antibacterial
impeded, ATP synthesis decreased Bacterial membrane disruption by the ampiphilic NPVP, leached silver ion from composite result in bacteria
[228]
1:1/21%: 17±9 nm
P. (-)
ACCEPTED aeruginosa BiofilmMANUSCRIPT formation 3×150 μL of 5 wt % death and 1:1 AgBr /21% inhibition biofilm NPVP composite formation coated surface
1:2/21%: 9±4 nm
IP
T
1:1/43%: 71±11 nm
CR
1:2/43%: 10±4 nm A. Baumannii (-)
Multi-drug resistant
MA N
Bare metal or < 5 nm metallic oxide (FESEM)
~30 μg Cu in bacteria Contact-killing liquid culture mechanism (high surface area to volume ratio) partially responsible for
CuO-NPs
Bare copper (II) 22.4-94.8 nm oxide (TEM)
AC
CE P
TE D
Cu-based-NPs carboxymethyl ated cotton
US
Copper based NPs
S. aureus (+)
Meticillin-resistant
1000 μg/mL (MBC assay)
S. aureus (+)
Epidemic
250-1000μg/mL
meticillin-resistant
(MBC assay)
Titanium based NPs 38
Without [148] cytotoxicity on NIH 3T3 cell
bacteria killing, interanalization of some degree of Cu Precise Gram-negativ mechanism of e strains action of showed a CuO-NPs is ongoing investigations
greater susceptibility to CuO-NPs combined with Ag-NPs
[229]
Nanofabritech)
dilution method) with UV light irradiation (365 nm, 370 μ W/cm2)
~ 40 nm
21% rutile)
MA N
E.oli (-) and K. pneumoniae (-)
TE D
~19 nm (SEM)
CE P
Not shown
Zinc oxide NPs ESBLs
AC
ZnO
Activation of TIO2 upon UV
Smaller size brookite
irradiation which produce radicals and anions to destruct organic substances
nanoparticles which promote nanoparticles to contact the bacteria cell membrane
Citing reference: more reactivity due to the nanoscale of
MIC value for E. coli and K. pneumonia: 500 μg/mL,
particle, adhesion on the bacteria membrane result in the damage of cell wall, production of ROS,
completely inhibit the bacterial growth at 1000 μg/mL
[163]
US
Not shown (purchased from Degussa Co.)
MANUSCRIPT S. aureusACCEPTED (+) Multi-drug resistant TiO2-NPs: 0.001-100 mg/mL (broth
T
45% anatase, 2% rutile, and 53% brookite) Commercial TiO2-NPs (P25-NPs, 79% anatase and
~10-15 nm
IP
Not shown (Supplied by
CR
TiO2-NPs (Br200-NPs,
NPs: 0-1000 μg/mL (colony forming assay)
penetration and internalization of NPs into bacteria Magnesium based NPs
39
[183]
Not shown
< 30 nm (TEM)
ACCEPTED MANUSCRIPT P. aeruginosa Antibiotic resistant NPs: 10-60 μg/mL (-), S. (MIC and MBC
Proposed mechanism:
None of NPs shown
pneumoniae(+) and S. aureus (+)
inhibition the production of β-lactamasae enzyme or the blocking of efflux pump pathway by MgO-NPs
sensitivity against the Streptococcus sp., CeO2-NPs showed no activity to all test pathogens
assay)
MgF2-NPs
Bare magnesium fluoride
MA N
US
CR
IP
T
MgO-NPs
E. coli (-), S. (HR-TEM), ~30 aureus (+)
Biofilm formation
20–25 nm
TE D
nm (XRD)
in MIC and MBC assay MgF2-NPs : ~0.023-1.5 mg/mL (antibiofilm activity assay)
Association on the cell surface, cell wall damage, penetrate into
CE P
cell, decrease in membrane potential, promotes the peroxidation of the lipids in the membrane
AC MgF2-NPs coated glass (microscope glass slides)
~25 nm (AFM)
MgF2-NPs completely coated on glass slid surface
40
[204]
Restricted bacterial colonization on the MgF2-NP coated glass for three days
[230]
ACCEPTED MANUSCRIPT Other metallic or metal oxide NPs
0.5 mV 14.9 ± 1.8 nm (DLS), -7.71 ±0.9 mV 19.93±1.31 nm (DLS), 8.65 ±
PEGylated SPIO-NPs
PEG750
Dimercaptosuc cinic acid
DMSA chelated
(DMSA) chelated SPIO-NPs
0.24 nm (XRD), 9.92 ± 3.14 nm (TEM), –35.5 mV Iron chelated via 23.32 ±1.17 nm DMSA (DLS), –34.0 mV
FeCl3 coated SPIO-NPs
ZnCl2 coated SPIO-NPs
ROS generation,
An external
(+)
biofilm formation
electrostatic interaction between metal NPs and bacteria
magnetic field applied to increase the penetration of biofilm
T
mg/mL (growth inhibition on adhering bacteria), CES-grafted SPIO-NPs: 0.35 mg/mL (magnetic effect during and
IP CR US
(DLS), 43.7 ± 1.7 mV APTES-grafted APTES 17.8 ± 2.6 nm SPIO-NPs (DLS), 32.6 ± 0.3 mV CES-grafted Carboxyethylsilan 13.8 ± 2.1 nm SPIO-NPs etriol (DLS), -15.4 ±
Gentamicin- resistant, Each SPIO-NPs: 0.35
MA N
SPIO-NPs
S. Epidermidis
S. aureus (+)
Biofilm formation
TE D
13.7 ± 2.1 nm
CE P
Bare iron oxide
AC
Bare
Zinc chelated via 19.67±0.72 nm DMSA (DLS), –40.1 mV
41
after biofilm formation)
[203]
No bacterial toxicity
Fe: 3.7-370 μg/mL (growth inhibition
Binding to the bacterial surface
Biofilm recovery at
and antibiofilm activity assay for each SPIO-NPs) Fe: 3.7-370 μg/mL, FeCl3 contain up to 0.002% Zn as
(SasG receptor) and blocking the formation of biofilm, penetrate into bacteria, releasing metal irons
higher zinc concentration, magnetic mediating biofilm penetration and separation
contamination Fe: 3.7-370 μg/mL, Zn: ~0.412-41.2μg/mL
intracellularly, decreasing intracellular bacillithiol,
of flocculated bacteria
[231]
~40nm (TEM)
S. epidermidis (+) and S. aureus (+)
Biofilm formation
Not shown
14–24 nm (TEM), 16 nm (XRD)
P. aeruginosa (+)
Biofilm formation
Al2O3-NPs
Not shown
< 50 nm (TEM)
P. aeruginosa (-), S.
Antibiotic resistant
Fe3O4-NPs
9-11 nm (TEM)
ZrO2-NPs
< 100 nm (TEM) < 25 nm (TEM)
pneumoniae(+) and S. aureus (+)
Not shown
< 40 nm (XRD)
TE D
2-4 mM (antibiofilm activity assay)
NPs: 10-60 μg/mL (MIC and MBC
reducing bacterial growth Upregulation of ROS production, deep penetration of biofilm using an external magnetic field
assay)
Methicillin-resistant
42
NPs: 0-500 μg (disc diffusion method)
[207]
[204]
sensitivity against the Streptococcus sp., CeO2-NPs showed no activity to all test pathogens
CE P
S. aureus (+)
No traces of [232] silver-coated SPIO NPs in mitochondria of cells (HepG2)
Cell lysis or disruption of cell wall structure Unrevealed None of NPs shown
AC
CeO2-NPs
MA N
CaO-NPs
Ag-doped MnO2
μg/mL Total metal ions: 80 μg/mL (bacteria growth inhibition)
CR
Ag-Au coated SPIO-NPs
Ag: ~1.126-112.57
T
Bare silver
mV ~20nm (TEM)
ACCEPTED MANUSCRIPT Fe: 3.7-370 μg/mL,
IP
Ag coated SPIO-NPs
Silver chelated 193.72±6.15 nm via DMSA (DLS), –43.2
US
AgNO3 coated SPIO-NPs
Formation of pits in the cell walls
in MIC and MBC assay There were no [233] zone of
ACCEPTED MANUSCRIPT P. aeruginosa Multidrug-resistant (-)
or breakdown of the cellularity
inhibition shown in the
W-NPs: 1500μg/mL (MIC assay)
Proposed mechanism:
presence of MnO2, Ni0.95Ag0.05O2 and Ce0.95Ag0.05O2 PVP as a stabilizer and PVP alone did not show any antibacterial activity.
2 mM (antibiofilm
inhibition of the microbial processes on the cell surface and within the cell Approximately 69% of cells were inactivated by the Bi-NPs which was not sufficient to form a biofilm
Bi-NPs for bacterial growth inhibition was 0.5 mM
Bare tungsten
8.1±2.8 nm (TEM)
E. coli (-) and S. Sulphamethoxazole aureus (+) and Cefotaxime-
Bi-NPs
Bare bismuth
3.3 ± 0.97 nm
S. mutans (+)
Biofilm formation
activity assay)
AC
CE P
(TEM)
TE D
MA N
resistant
US
W-NPs
CR
IP
T
(Mn0.95Ag0.05O 2)
MIC of
[206]
[205]
PACT: photodynamic antimicrobial chemotherapy, PDT: photodynamic therapy, NIR: near-infrared radiation, SPIO: superparamagnetic iron oxide, TEM: transmission electron microscopy, XRD: X-ray diffraction, MIC: Minimum inhibitory concentration, MBC: Minimum Bactericidal Concentration, ESBLs: extended-spectrum β-lactamases, NSP: nanoscale silicate platelets, PAA: polyacrylic acid, APTES: 3-Aminopropyltriethoxysilane, CES: carboxyethylsilanetriol sodium, PEG750: Polyethylene glycol 750, PVP: poly-(N-vinyl-2-pyrrolidone), NPVP: poly(4-vinylpyridine)-co-poly(4-vinyl-N-hexylpyridinium bromide)
43
ACCEPTED MANUSCRIPT
Au (4, 10, 28, and 58 nm)
137.5-2200 μg/kg
MA N
High concentration Au NPs decreased body
intraperitoneal and tail
for 14–28 days
weight, red blood cells, hematocrit. Oral
TE D
Oral administration,
AC
Intraperitoneal injection
[234]
[235]
administration decreased in body weight,
CE P 30, and 60 nm)
5, 10,
References
liver, spleen, lung, brain. Larger NPs were accumulated in the gastrointestinal tract.
vein injection
Au NPs (PEG-coated,
Physiology and histopathology changes
200 μg/kg for 7 Smaller NPs were accumulated in kidney,
Oral administration
days
Au (13.5nm)
IP
Does /duration
CR
Administration route
US
Mental NPs/size
T
Table 2. Toxicities of metal NPs assessed in vivo.
spleen index, and red blood cells. No change at low concentration.
4 mg/kg for 28
5 nm and 10 nm Au NPs mainly
days
accumulated in liver and decreased white blood cells. 30 nm Au NPs accumulated in spleen. 60 nm Au NPs caused liver and kidney damage.
44
[236]
75 , 150 and 300
No effect in blood chemistry, body weight
ppm for 28 days
T
Oral administration
[237]
and organ histology.
Ag NPs (22 nm, 42 nm, 71 nm
Oral administration
Oral administration
The concentration at 125 mg/ml caused liver
mg/kg for 90 days
damage.
1 mg/kg for 14
Smaller size Ag NPs were distributed to
days
brain, lung, liver, kidney, and testis.
TE D
and 323nm)
30, 125 and 500
MA N
Ag (56nm)
US
CR
Au NPs (14nm)
IP
ACCEPTED MANUSCRIPT
Cu (25nm)
Oral administration
[239]
Larger size Ag NPs were not detected in
CE P
Oral administration
AC
Cu (23.5nm)
[238]
tissues.
108 and 1,080 mg/kg
kidney, liver, and spleen severe injury
[240]
50 and 200 mg/kg
Liver and kidney damage
[241]
62.5, 125 and 250
Body weight decreased and liver damage,
[242]
mg/kg for 14 days
pathological blood count at ≥125 mg/kg
for 5 days TiO2 (5nm)
Intraperitoneal injection
45
ACCEPTED MANUSCRIPT
5, 50 and 150
Spleen injury
T
Intraperitoneal injection
Oral administration
160, 400 and 1000
US
TiO2 NPs (＜50nm)
CR
mg/kg for 45 days
The concentration at 1g/kg caused liver
[244]
damage, disturbance of energy and amino acid metabolism.
324, 648, 972,
Spleen, liver and kidney damage, thrombosis [245]
injection
1296, 1944 and
detected in the pulmonary vascular system in
2592mg/ kg for 24,
high dose concentration.
TE D
Intraperitioneal
CE P
TiO2 (80, 110 and 100 nm)
MA N
mg/kg for 15 days
[243]
IP
TiO2 (6 to 7nm)
48 hours, 7 and 14
ZnO (20nm and 120nM)
ZnO (50, 70 and <1,000 nm)
AC
days
Oral administration
Instillation
1, 2, 3, 4 and 5
Zn was mainly accumulated in the bone,
g/kg for 14 days
kidney and pancreas.
1 and 5mg/kg for
Reversible inflammatory response
24hours, 1week, 1 and 3 months
46
[246]
[247]
ACCEPTED MANUSCRIPT Acknowledgements This
work
was
founded
by
National
Health
Research
Institutes
IP
T
(NHRI-EX102-10114EC) and National Science Council.
SC R
References [1] M.L. Cohen, Changing patterns of infectious disease, Nature, 406 (2000) 762-767. [2] A.J. Huh, Y.J. Kwon, "Nanoantibiotics": a new paradigm for treating infectious
MA
NU
diseases using nanomaterials in the antibiotics resistant era, J Control Release, 156 (2011) 128-145. [3] P.J. Highton, D.G. Hobbs, Penicillin and cell wall synthesis: a study of Bacillus cereus by electron microscopy, J Bacteriol, 109 (1972) 1181-1190. [4] D.L. Goldman, Vancomycin, Pediatrics in Review, 16 (1995) 357-358. [5] H.W. Taber, J.P. Mueller, P.F. Miller, A.S. Arrow, Bacterial uptake of aminoglycoside
D
antibiotics, Microbiol Rev, 51 (1987) 439-457. [6] X.S. Pan, L.M. Fisher, Streptococcus pneumoniae DNA gyrase and topoisomerase IV: overexpression, purification, and differential inhibition by fluoroquinolones,
AC
CE P
TE
Antimicrob Agents Ch, 43 (1999) 1129-1136. [7] E. Battaner, B.V. Kumar, Rifampin: inhibition of ribonucleic acid synthesis after potentiation by amphotericin B in Saccharomyces cerevisiae, Antimicrob Agents Ch, 5 (1974) 371-376. [8] E.P. Quinlivan, McPartlin, J., Donald G,. Scott, J., Mechanism of the antimicrobial drug trimethoprim revisited, The FASEB Journal, 14 (2000) 2519-2524. [9] S.S. Richter, D.E. Kealey, C.T. Murray, K.P. Heilmann, S.L. Coffman, G.V. Doern, The in vitro activity of daptomycin against staphylococcus aureus and enterococcus species, J Antimicrob Chemother, 52 (2003) 123-127. [10] W. Witte, International dissemination of antibiotic resistant strains of bacterial pathogens, Infection, Genetics and Evolution, 4 (2004) 187-191. [11] M.A. Riley, S.M. Robinson, C.M. Roy, M. Dennis, V. Liu, R.L. Dorit, Resistance is futile: the bacteriocin model for addressing the antibiotic resistance challenge, Biochem Soc Trans, 40 (2012) 1438-1442. [12] C. Baker-Austin, M.S. Wright, R. Stepanauskas, J.V. McArthur, Co-selection of antibiotic and metal resistance, Trends Microbiol, 14 (2006) 176-182. [13] D.A. Tadesse, S. Zhao, E. Tong, S. Ayers, A. Singh, M.J. Bartholomew, P.F. McDermott, Antimicrobial drug resistance in Escherichia coli from humans and food animals, United States, 1950-2002, Emerg Infect Dis, 18 (2012) 741-749. [14] P. Baptista, E. Pereira, P. Eaton, G. Doria, A. Miranda, I. Gomes, P. Quaresma, R. Franco, Gold nanoparticles for the development of clinical diagnosis methods, Anal 47
ACCEPTED MANUSCRIPT
SC R
IP
T
Bioanal Chem, 391 (2008) 943-950. [15] L.R. Hirsch, R.J. Stafford, J.A. Bankson, S.R. Sershen, B. Rivera, R.E. Price, J.D. Hazle, N.J. Halas, J.L. West, Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance, Proc Natl Acad Sci U S A, 100 (2003) 13549-13554. [16] G. Han, P. Ghosh, V. Rotello, Multi-Functional gold nanoparticles for drug delivery, in: W.W. Chan (Ed.) Bio-Applications of Nanoparticles, Springer New York, 2007, pp. 48-56. [17] R.P. Allaker, G. Ren, Potential impact of nanotechnology on the control of
MA
NU
infectious diseases, R Soc Trop Med Hyg, 102 (2008) 1-2. [18] A. Rai, A. Prabhune, C.C. Perry, Antibiotic mediated synthesis of gold nanoparticles with potent antimicrobial activity and their application in antimicrobial coatings, J Materials Chemistry, 20 (2010) 6789-6798. [19] C.M. Goodman, C.D. McCusker, T. Yilmaz, V.M. Rotello, Toxicity of gold
D
nanoparticles functionalized with cationic and anionic side chains, Bioconjugate Chem, 15 (2004) 897-900. [20] G.M. Whitesides, Nanoscience, nanotechnology, and chemistry, Small, 1 (2005) 172-179.
AC
CE P
TE
[21] K.R. Raghupathi, R.T. Koodali, A.C. Manna, Size-dependent bacterial growth inhibition and mechanism of antibacterial activity of zinc oxide nanoparticles, Langmuir, 27 (2011) 4020-4028. [22] L. Zhang, D. Pornpattananangku, C.M. Hu, C.M. Huang, Development of nanoparticles for antimicrobial drug delivery, Curr Med Chem, 17 (2010) 585-594. [23] C.H. Huang, Chen, C.H., Dissaya, P., Li, Z., Chan, M., Hsieh, M.F., Zhang, L., Eradication of drug resistant Staphylococcus aureus by liposomal oleic acids, Biomaterials, 32 (2011) 214-221. [24] M.J. Hajipour, K.M. Fromm, A. Akbar Ashkarran, D. Jimenez de Aberasturi, I.R.d. Larramendi, T. Rojo, V. Serpooshan, W.J. Parak, M. Mahmoudi, Antibacterial properties of nanoparticles, Trends Biotechnol, 30 (2012) 499-511. [25] J.G. Leid, A.J. Ditto, A. Knapp, P.N. Shah, B.D. Wright, R. Blust, L. Christensen, C.B. Clemons, J.P. Wilber, G.W. Young, A.G. Kang, M.J. Panzner, C.L. Cannon, Y.H. Yun, W.J. Youngs, N.M. Seckinger, E.K. Cope, In vitro antimicrobial studies of silver carbene complexes: activity of free and nanoparticle carbene formulations against clinical isolates of pathogenic bacteria, J Antimicrob Chemother, 67 (2012) 138-148. [26] S.T. Harrison JW, The beginning of the end of the antibiotic era? Part II. Proposed solutions to antibiotic abuse, Quintessence Int, 29 (1998) 223-229. [27] D.L. Smith, A.D. Harris, J.A. Johnson, E.K. Silbergeld, J.G. Morris, Jr., Animal antibiotic use has an early but important impact on the emergence of antibiotic 48
ACCEPTED MANUSCRIPT
SC R
IP
T
resistance in human commensal bacteria, Proc Natl Acad Sci U S A, 99 (2002) 6434-6439. [28] P.J. James, I.A. Butcher, E.R. Gardner, D.L. Hamblen, Methicillin-resistant Staphylococcus epidermidis in infection of hip arthroplasties, J Bone Joint Surg Br, 76 (1994) 725-727. [29] P.Y. Litzler, L. Benard, N. Barbier-Frebourg, S. Vilain, T. Jouenne, E. Beucher, C. Bunel, J.F. Lemeland, J.P. Bessou, Biofilm formation on pyrolytic carbon heart valves: influence of surface free energy, roughness, and bacterial species, J Thorac Cardiovasc Surg, 134 (2007) 1025-1032.
MA
NU
[30] A. Percival, W. Brumfitt, J. De Louvois, The role of penicillinase in determining natural and acquired resistance of Gram-negative bacteria to penicillins, J Gen Microbiol, 32 (1963) 77-89. [31] H. Yoneyama, R. Katsumata, Antibiotic resistance in bacteria and its future for novel antibiotic development, Biosci Biotech Bioch, 70 (2006) 1060-1075.
D
[32] G.D. Wright, Bacterial resistance to antibiotics: enzymatic degradation and modification, Adv Drug Deliv Rev, 57 (2005) 1451-1470. [33] K. Ochiai, T. Yamanaka, K. Kimura, O. Sawada, Inheritance of drug resistance (and its transfer) between Shigella strains and between Shigella and E. coli strains (in
AC
CE P
TE
Japanese), Hihon Iji Shimpor, 1861 (1959) 34. [34] E.V. Koonin, K.S. Makarova, L. Aravind, Horizontal gene transfer in prokaryotes: quantification and classification, Annu Rev Microbiol, 55 (2001) 709-742. [35] K.M. Nielsen, Barriers to horizontal gene transfer by natural transformation in soil bacteria, APMIS Suppl, 84 (1998) 77-84. [36] K. Poole, Mechanisms of bacterial biocide and antibiotic resistance, J Appl Microbiol, 92 (2002) 55s-64s. [37] R. Jayaraman, Antibiotic resistance: an overview of mechanisms and a paradigm shift, Curr Sci India, 96 (2009) 1475-1484. [38] E.P. Abraham, E. Chain, An enzyme from bacteria able to destroy penicillin. 1940, Rev Infect Dis, 10 (1988) 677-678. [39] G.W. Kaatz, S.M. Seo, C.A. Ruble, Efflux-mediated fluoroquinolone resistance in Staphylococcus aureus, Antimicrob Agents Ch, 37 (1993) 1086-1094. [40] L. Ferrero, B. Cameron, J. Crouzet, Analysis of gyrA and grlA mutations in stepwise-selected ciprofloxacin-resistant mutants of Staphylococcus aureus, Antimicrob Agents Ch, 39 (1995) 1554-1558. [41] E.Y. Ng, M. Trucksis, D.C. Hooper, Quinolone resistance mutations in topoisomerase IV: relationship to the flqA locus and genetic evidence that topoisomerase IV is the primary target and DNA gyrase is the secondary target of fluoroquinolones in Staphylococcus aureus, Antimicrob Agents Ch, 40 (1996) 49
ACCEPTED MANUSCRIPT
SC R
IP
T
1881-1888. [42] M. Takahata, M. Yonezawa, S. Kurose, N. Futakuchi, N. Matsubara, Y. Watanabe, H. Narita, Mutations in the gyrA and grlA genes of quinolone-resistant clinical isolates of methicillin-resistant Staphylococcus aureus, J Antimicrob Chemother, 38 (1996) 543-546. [43] K. Bockstael, A. Van Aerschot, Antimicrobial resistance in bacteria, Cent Eur J Med, 4 (2009) 141-155. [44] W.W. Spink, L.D. Wright, J.J. Vivino, H.R. Skeggs, Para-aminobenzoic acid production by Staphylococci, J Exp Med, 79 (1944) 331-339.
MA
NU
[45] D.H. Deck, L.G., Winston, Sulfonamides, trimethoprim, & quinolones, in:B. Katzung, S. Masters, A. Trevor (Eds.), in: Basic and clinical pharmacology,12th ed, 2012, pp. 831–838. [46] P. Iliades, S.R. Meshnick, I.G. Macreadie, Dihydropteroate synthase mutations in Pneumocystis jiroveci can affect sulfamethoxazole resistance in a saccharomyces
D
cerevisiae model, Antimicrob Agents Ch, 48 (2004) 2617-2623. [47] J. Lubelski, W.N. Konings, A.J. Driessen, Distribution and physiology of ABC-type transporters contributing to multidrug resistance in bacteria, Microbiol Mol Biol Rev, 71 (2007) 463-476.
AC
CE P
TE
[48] S.S. Pao, I.T. Paulsen, M.H. Saier, Jr., Major facilitator superfamily, Microbiol Mol Biol Rev, 62 (1998) 1-34. [49] T. Kuroda, T. Tsuchiya, Multidrug efflux transporters in the MATE family, Biochim Biophys Acta, 1794 (2009) 763-768. [50] D.L. Jack, N.M. Yang, M.H. Saier, Jr., The drug/metabolite transporter superfamily, Eur J Biochem, 268 (2001) 3620-3639. [51] X.Z. Li, H. Nikaido, Efflux-mediated drug resistance in bacteria, Drugs, 64 (2004) 159-204. [52] J. Palmer, S. Flint, J. Brooks, Bacterial cell attachment, the beginning of a biofilm, J Ind Microbiol Biotechnol, 34 (2007) 577-588. [53] R.M. Donlan, Biofilm formation: a clinically relevant microbiological process, Clin Infect Dis, 33 (2001) 1387-1392. [54] C.R. Arciola, D. Campoccia, P. Speziale, L. Montanaro, J.W. Costerton, Biofilm formation in Staphylococcus implant infections. A review of molecular mechanisms and implications for biofilm-resistant materials, Biomaterials, 33 (2012) 5967-5982. [55] M. Hentzer, L. Eberl, M. Givskov, Transcriptome analysis of pseudomonas aeruginosa biofilm development: anaerobic respiration and iron limitation, Biofilms, 2 (2005) 37-61. [56] T.R. Garrett, M. Bhakoo, Z. Zhang, Characterisation of bacterial adhesion and removal in a flow chamber by micromanipulation measurements, Biotechnol Lett, 30 50
ACCEPTED MANUSCRIPT
SC R
IP
T
(2008) 427-433. [57] W.M. Dunne, Jr., Bacterial adhesion: seen any good biofilms lately?, Clin Microbiol Rev, 15 (2002) 155-166. [58] M.B. Miller, B.L. Bassler, Quorum sensing in bacteria, Annu Rev Microbiol, 55 (2001) 165-199. [59] F. Harrison, Microbial ecology of the cystic fibrosis lung, Microbiology, 153 (2007) 917-923. [60] F.C. Petersen, L. Tao, A.A. Scheie, DNA binding-uptake system: a link between cell-to-cell communication and biofilm formation, J Bacteriol, 187 (2005) 4392-4400.
MA
NU
[61] S. Park, P.M. Wolanin, E.A. Yuzbashyan, H. Lin, N.C. Darnton, J.B. Stock, P. Silberzan, R. Austin, Influence of topology on bacterial social interaction, Proc Natl Acad Sci U S A, 100 (2003) 13910-13915. [62] G. O'Toole, H.B. Kaplan, R. Kolter, Biofilm formation as microbial development, Annu Rev Microbiol, 54 (2000) 49-79.
D
[63] J.W. Costerton, P.S. Stewart, E.P. Greenberg, Bacterial biofilms: a common cause of persistent infections, Science, 284 (1999) 1318-1322. [64] M.R. Parsek, P.K. Singh, Bacterial biofilms: An emerging link to disease pathogenesis, Annu Rev Microbiol, 57 (2003) 677-701.
AC
CE P
TE
[65] P.S. Stewart, Mechanisms of antibiotic resistance in bacterial biofilms, Int J Med Microbiol, 292 (2002) 107-113. [66] B.D. Hoyle, C.K. Wong, J.W. Costerton, Disparate efficacy of tobramycin on Ca(2+)-, Mg(2+)-, and HEPES-treated pseudomonas aeruginosa biofilms, Can J Microbiol, 38 (1992) 1214-1218. [67] I.G. Duguid, E. Evans, M.R. Brown, P. Gilbert, Effect of biofilm culture upon the susceptibility of staphylococcus epidermidis to tobramycin, J Antimicrob Chemother, 30 (1992) 803-810. [68] D.J. Evans, D.G. Allison, M.R.W. Brown, P. Gilbert, Effect of growth-rate on resistance of gram-negative biofilms to cetrimide, J Antimicrob Chemother, 26 (1990) 473-478. [69] H. Anwar, J.L. Strap, K. Chen, J.W. Costerton, Dynamic interactions of biofilms of mucoid pseudomonas aeruginosa with tobramycin and piperacillin, Antimicrob Agents Ch, 36 (1992) 1208-1214. [70] B. Poolman, E. Glaasker, Regulation of compatible solute accumulation in bacteria, Mol Microbiol, 29 (1998) 397-407. [71] G. Storz, J.A. Imlayt, Oxidative stress, Curr Opin Microbiol, 2 (1999) 188-194. [72] O. Tresse, T. Jouenne, G.-A. Junter, The role of oxygen limitation in the resistance of agar-entrapped, sessile-like Escherichia coli to aminoglycoside and β-lactam antibiotics, J Antimicrob Chemother, 36 (1995) 521-526. 51
ACCEPTED MANUSCRIPT
SC R
IP
T
[73] A.L. Spoering, K. Lewis, Biofilms and planktonic cells of pseudomonas aeruginosa have similar resistance to killing by antimicrobials, J Bacteriol, 183 (2001) 6746-6751. [74] K.Y. Yoon, J. Hoon Byeon, J.H. Park, J. Hwang, Susceptibility constants of escherichia coli and bacillus subtilis to silver and copper nanoparticles, Sci Total Environ, 373 (2007) 572-575. [75] J.P. Ruparelia, A.K. Chatterjee, S.P. Duttagupta, S. Mukherji, Strain specificity in antimicrobial activity of silver and copper nanoparticles, Acta Biomater, 4 (2008) 707-716. [76] P.K. Stoimenov, R.L. Klinger, G.L. Marchin, K.J. Klabunde, Metal oxide
MA
NU
nanoparticles as bactericidal agents, Langmuir, 18 (2002) 6679-6686. [77] K.R. Raghupathi, R.T. Koodali, A.C. Manna, Size-dependent bacterial growth inhibition and mechanism of antibacterial activity of zinc oxide nanoparticles, Langmuir, 27 (2011) 4020-4028. [78] R.P. Feynman, There's plenty of room at the bottom, Science, 254 (1991)
D
1300-1301. [79] I.C. Shaw, Gold-based therapeutic agents, Chem Rev, 99 (1999) 2589-2600. [80] A.E. Finkelstein, D.T. Walz, V. Batista, M. Mizraji, F. Roisman, A. Misher, Auranofin. New oral gold compound for treatment of rheumatoid arthritis, Ann
AC
CE P
TE
Rheum Dis, 35 (1976) 251-257. [81] M.A. El-Sayed, Some interesting properties of metals confined in time and nanometer space of different shapes, Acc Chem Res, 34 (2001) 257-264. [82] E. Hutter, J.H. Fendler, D. Roy, Surface plasmon resonance studies of gold and silver nanoparticles linked to gold and silver substrates by 2-aminoethanethiol and 1,6-hexanedithiol, J Phys Chem B, 105 (2001) 11159-11168. [83] J. Wang, G. Zhu, M. You, E. Song, M.I. Shukoor, K. Zhang, M.B. Altman, Y. Chen, Z. Zhu, C.Z. Huang, W. Tan, Assembly of aptamer switch probes and photosensitizer on gold nanorods for targeted photothermal and photodynamic cancer therapy, ACS Nano, 6 (2012) 5070-5077. [84] T.A. El-Brolossy, T. Abdallah, M.B. Mohamed, S. Abdallah, K. Easawi, S. Negm, H. Talaat, Shape and size dependence of the surface plasmon resonance of gold nanoparticles studied by photoacoustic technique, Eur Phys J Spec Top, 153 (2008) 361-364. [85] J. Lin, S. Wang, P. Huang, Z. Wang, S. Chen, G. Niu, W. Li, J. He, D. Cui, G. Lu, X. Chen, Z. Nie, Photosensitizer-loaded gold vesicles with strong plasmonic coupling effect for imaging-guided photothermal/photodynamic therapy, ACS Nano, 7 (2013) 5320-5329. [86] V.D. Badwaik, L.M. Vangala, D.S. Pender, C.B. Willis, Z.P. Aguilar, M.S. Gonzalez, R. Paripelly, R. Dakshinamurthy, Size-dependent antimicrobial properties of 52
ACCEPTED MANUSCRIPT
SC R
IP
T
sugar-encapsulated gold nanoparticles synthesized by a green method, Nanoscale Res Lett, 7 (2012) 623. [87] D. Pissuwan, C.H. Cortie, S.M. Valenzuela, M.B. Cortie, Functionalised gold nanoparticles for controlling pathogenic bacteria, Trends Biotechnol, 28 (2010) 207-213. [88] W.S. Kuo, C.N. Chang, Y.T. Chang, C.S. Yeh, Antimicrobial gold nanorods with dual-modality photodynamic inactivation and hyperthermia, Chem Commun (Camb), (2009) 4853-4855. [89] S. Wang, A.K. Singh, D. Senapati, A. Neely, H. Yu, P.C. Ray, Rapid colorimetric
MA
NU
identification and targeted photothermal lysis of salmonella bacteria by using bioconjugated oval-shaped gold nanoparticles, Chem Eur J, 16 (2010) 5600-5606. [90] G.A. Nirmala, K. Pandian, Antibacterial efficacy of aminoglycosidic antibiotics protected gold nanoparticles—A brief study, Colloid Surf A-Physicochem Eng Asp, 297 (2007) 63-70.
D
[91] G.L. Burygin, B.N. Khlebtsov, A.N. Shantrokha, L.A. Dykman, V.A. Bogatyrev, N.G. Khlebtsov, On the enhanced antibacterial activity of antibiotics mixed with gold nanoparticles, Nanoscale Res Lett, 4 (2009) 794-801. [92] M. Chamundeeswari, S.S. Sobhana, J.P. Jacob, M.G. Kumar, M.P. Devi, T.P. Sastry,
AC
CE P
TE
A.B. Mandal, Preparation, characterization and evaluation of a biopolymeric gold nanocomposite with antimicrobial activity, Biotechnol Appl Biochem, 55 (2010) 29-35. [93] V.P. Zharov, K.E. Mercer, E.N. Galitovskaya, M.S. Smeltzer, Photothermal nanotherapeutics and nanodiagnostics for selective killing of bacteria targeted with gold nanoparticles, Biophys J, 90 (2006) 619-627. [94] R.S. Norman, J.W. Stone, A. Gole, C.J. Murphy, T.L. Sabo-Attwood, Targeted photothermal lysis of the pathogenic bacteria, pseudomonas aeruginosa, with gold nanorods, Nano Lett, 8 (2008) 302-306. [95] W.C. Huang, P.-J. Tsai, Y.C. Chen, Functional gold nanoparticles as photothermal agents for selective-killing of pathogenic bacteria, Nanomedicine, 2 (2007) 777-787. [96] J. Gil-Tomas, S. Tubby, I.P. Parkin, N. Narband, L. Dekker, S.P. Nair, M. Wilson, C. Street, lethal photosensitisation of staphylococcus aureus using a toluidine blue o-tiopronin-gold nanoparticle conjugate, J Mater Chem, 17 (2007) 3739-3746. [97] H. Gu, P.L. Ho, E. Tong, L. Wang, B. Xu, Presenting vancomycin on nanoparticles to enhance antimicrobial activities, Nano Lett, 3 (2003) 1261-1263. [98] A.N. Brown, K. Smith, T.A. Samuels, J.R. Lu, S.O. Obare, M.E. Scott, Nanoparticles functionalized with ampicillin destroy multiple-antibiotic-resistant isolates of pseudomonas aeruginosa and enterobacter aerogenes and methicillin-resistant staphylococcus aureus, Appl Environ Microb, 78 (2012) 2768-2774. 53
ACCEPTED MANUSCRIPT
SC R
IP
T
[99] Y. Cui, Y. Zhao, Y. Tian, W. Zhang, X. Lu, X. Jiang, The molecular mechanism of action of bactericidal gold nanoparticles on escherichia coli, Biomaterials, 33 (2012) 2327-2333. [100] Y. Zhou, Y. Kong, S. Kundu, J.D. Cirillo, H. Liang, Antibacterial activities of gold and silver nanoparticles against escherichia coli and bacillus calmette-guerin, J Nanobiotechnology, 10 (2012) 19. [101] T.J. Berger, J.A. Spadaro, S.E. Chapin, R.O. Becker, Electrically generated silver ions: quantitative effects on bacterial and mammalian cells, Antimicrob Agents Ch, 9 (1976) 357-358.
MA
NU
[102] R. Slawson, J. Trevors, H. Lee, Silver accumulation and resistance in pseudomonas stutzeri, Arch Microbiol, 158 (1992) 398-404. [103] G. Zhao, Edward Stevens Jr, S., Multiple parameters for the comprehensive evaluation of the susceptibility of escherichia coli to the silver ion, Biometals, 11 (1998) 27-32.
D
[104] S. Silver, L.T. Phung, Bacterial heavy metal resistance: new surprises, Annu Rev Microbiol, 50 (1996) 753-789. [105] J.H. Crabtree, R.J. Burchette, R.A. Siddiqi, I.T. Huen, L.L. Hadnott, A. Fishman, The efficacy of silver-ion implanted catheters in reducing peritoneal dialysis-related
AC
CE P
TE
infections, Perit Dial Int, 23 (2003) 368-374. [106] K. Dunn, V. Edwards-Jones, The role of Acticoat with nanocrystalline silver in the management of burns, Burns, 30 Suppl 1 (2004) S1-9. [107] A. Petica, S. Gavriliu, M. Lungu, N. Buruntea, C. Panzaru, Colloidal silver solutions with antimicrobial properties, Mater Sci Eng B, 152 (2008) 22-27. [108] M. Rai, A. Yadav, A. Gade, Silver nanoparticles as a new generation of antimicrobials, Biotechnol Adv, 27 (2009) 76-83. [109] P. Jain, T. Pradeep, Potential of silver nanoparticle-coated polyurethane foam as an antibacterial water filter, Biotechnol Bioeng, 90 (2005) 59-63. [110] M. Ip, S.L. Lui, V.K. Poon, I. Lung, A. Burd, Antimicrobial activities of silver dressings: an in vitro comparison, J Med Microbiol, 55 (2006) 59-63. [111] C. Aymonier, U. Schlotterbeck, L. Antonietti, P. Zacharias, R. Thomann, J.C. Tiller, S. Mecking, Hybrids of silver nanoparticles with amphiphilic hyperbranched macromolecules exhibiting antimicrobial properties, Chem Commun (Camb), (2002) 3018-3019. [112] J. Tian, K.K.Y. Wong, C.M. Ho, C.N. Lok, W.Y. Yu, C.M. Che, P.K.H. Tam, Topical delivery of silver nanoparticles promotes wound healing, ChemMedChem, 2 (2007) 129-136. [113] P. Pallavicini, A. Taglietti, G. Dacarro, Y. Antonio Diaz-Fernandez, M. Galli, P. Grisoli, M. Patrini, G. Santucci De Magistris, R. Zanoni, Self-assembled monolayers of 54
ACCEPTED MANUSCRIPT
SC R
IP
T
silver nanoparticles firmly grafted on glass surfaces: low Ag+ release for an efficient antibacterial activity, J Colloid Interface Sci, 350 (2010) 110-116. [114] S. Chernousova, M. Epple, Silver as antibacterial agent: Ion, nanoparticle, and metal, Angew Chem Int Edit, 52 (2013) 1636-1653. [115] H.H. Lara, N.V. Ayala-Nunez, L.D.I. Turrent, C.R. Padilla, Bactericidal effect of silver nanoparticles against multidrug-resistant bacteria, World J Microb Biot, 26 (2010) 615-621. [116] S.L. Percival, P.G. Bowler, J. Dolman, Antimicrobial activity of silver-containing dressings on wound microorganisms using an in vitro biofilm model, Int Wound J, 4
MA
NU
(2007) 186-191. [117] H.H. Lara, N.V. Ayala-Nunez, L. Ixtepan-Turrent, C. Rodriguez-Padilla, Mode of antiviral action of silver nanoparticles against HIV-1, J Nanobiotechnology, 8 (2010) 1. [118] K.J. Kim, W.S. Sung, S.K. Moon, J.S. Choi, J.G. Kim, D.G. Lee, Antifungal effect of silver nanoparticles on dermatophytes, J Microbiol Biotechnol, 18 (2008) 1482-1484.
D
[119] H.L. Su, S.H. Lin, J.C. Wei, I.C. Pao, S.H. Chiao, S.Z. Lin, J.J. Lin, Novel nanohybrids of silver particles on clay platelets for inhibiting silver-resistant bacteria, PLoS One, 6 (2011) e21125. [120] J.R. Morones, J.L. Elechiguerra, A. Camacho, K. Holt, J.B. Kouri, J.T. Ramirez, M.J.
AC
CE P
TE
Yacaman, The bactericidal effect of silver nanoparticles, Nanotechnology, 16 (2005) 2346-2353. [121] I. Sondi, B. Salopek-Sondi, Silver nanoparticles as antimicrobial agent: a case study on E. coli as a model for gram-negative bacteria, J Colloid Interface Sci, 275 (2004) 177-182. [122] S. Shrivastava, T. Bera, A. Roy, G. Singh, P. Ramachandrarao, D. Dash, Characterization of enhanced antibacterial effects of novel silver nanoparticles, Nanotechnology, 18 (2007) 1-9. [123] M.L.W. Knetsch, L.H. Koole, New strategies in the development of antimicrobial coatings: The example of increasing usage of silver and silver nanoparticles, Polymers, 3 (2011) 340-366. [124] J.S. Kim, E. Kuk, K.N. Yu, J.H. Kim, S.J. Park, H.J. Lee, S.H. Kim, Y.K. Park, Y.H. Park, C.Y. Hwang, Antimicrobial effects of silver nanoparticles, Nanomed Nanotech Biol Med, 3 (2007) 95-101. [125] Q.L. Feng, J. Wu, G.Q. Chen, F.Z. Cui, T.N. Kim, J.O. Kim, A mechanistic study of the antibacterial effect of silver ions on escherichia coli and staphylococcus aureus, J Biomed Mater Res, 52 (2000) 662-668. [126] Y. Matsumura, K. Yoshikata, S.i. Kunisaki, T. Tsuchido, Mode of bactericidal action of silver zeolite and its comparison with that of silver nitrate, Appl Environ Microb, 69 (2003) 4278-4281. 55
ACCEPTED MANUSCRIPT
SC R
IP
T
[127] D.W. Hatchett, H.S. White, Electrochemistry of sulfur adlayers on the low-index faces of silver, J Phys Chem, 100 (1996) 9854-9859. [128] Y.-H. Hsin, C.-F. Chen, S. Huang, T.-S. Shih, P.-S. Lai, P.J. Chueh, The apoptotic effect of nanosilver is mediated by a ROS- and JNK-dependent mechanism involving the mitochondrial pathway in NIH3T3 cells, Toxicol Lett, 179 (2008) 130-139. [129] C. Rensing, G. Grass, Escherichia coli mechanisms of copper homeostasis in a changing environment, FEMS Microbiol Rev, 27 (2003) 197-213. [130] A.S. Gordon, L.D. Howell, V. Harwood, Responses of diverse heterotrophic bacteria to elevated copper concentrations, Can J Microbiol, 40 (1994) 408-411.
MA
NU
[131] C. Espírito Santo, P.V. Morais, G. Grass, Isolation and characterization of bacteria resistant to metallic copper surfaces, Appl Environ Microb, 76 (2010) 1341-1348. [132] K. Karlin, Metalloenzymes, structural motifs, and inorganic models, Science, 261 (1993) 701-708.
D
[133] G. Grass, C. Rensing, M. Solioz, Metallic copper as an antimicrobial surface, Appl Environ Microb, 77 (2011) 1541-1547. [134] L. Macomber, J.A. Imlay, The iron-sulfur clusters of dehydratases are primary intracellular targets of copper toxicity, Proc Natl Acad Sci U S A, 106 (2009)
AC
CE P
TE
8344-8349. [135] L.J. Wheeldon, T. Worthington, P.A. Lambert, A.C. Hilton, C.J. Lowden, T.S.J. Elliott, Antimicrobial efficacy of copper surfaces against spores and vegetative cells of clostridium difficile: the germination theory, J Antimicrob Chemother, 62 (2008) 522-525. [136] S. Mehtar, I. Wiid, S.D. Todorov, The antimicrobial activity of copper and copper alloys against nosocomial pathogens and mycobacterium tuberculosis isolated from healthcare facilities in the western cape: an in-vitro study, J hosp infect, 68 (2008) 45-51. [137] M. Ibrahim, F. Wang, M.-m. Lou, G.-l. Xie, B. Li, Z. Bo, G.-q. Zhang, H. Liu, A. Wareth, Copper as an antibacterial agent for human pathogenic multidrug resistant burkholderia cepacia complex bacteria, J Biosci Bioeng, 112 (2011) 570-576. [138] G. Faundez, M. Troncoso, P. Navarrete, G. Figueroa, Antimicrobial activity of copper surfaces against suspensions of salmonella enterica and campylobacter jejuni, BMC Microbiol, 4 (2004) 19. [139] C.E. Santo, N. Taudte, D.H. Nies, G. Grass, Contribution of copper Ion resistance to survival of Escherichia coli on metallic copper surfaces, Appl Environ Microb, 74 (2008) 977-986. [140] W.-X. Tian, S. Yu, M. Ibrahim, A. Almonaofy, L. He, Q. Hui, Z. Bo, B. Li, G.-l. Xie, Copper as an antimicrobial agent against opportunistic pathogenic and multidrug 56
ACCEPTED MANUSCRIPT
SC R
IP
T
resistant Enterobacter bacteria, J Microbiol, 50 (2012) 586-593. [141] J.O. Noyce, H. Michels, C.W. Keevil, Potential use of copper surfaces to reduce survival of epidemic meticillin-resistant staphylococcus aureus in the healthcare environment, J hosp infect, 63 (2006) 289-297. [142] G. Steindl, , S. Heuberger, B. Springer, Antimicrobial effect of copper on multidrug-resistant bacteria, Wien Tierarztl Monat, 99 (2012) 38-43. [143] C.E. Santo, E.W. Lam, C.G. Elowsky, D. Quaranta, D.W. Domaille, C.J. Chang, G. Grass, Bacterial killing by dry metallic copper surfaces, Appl Environ Microb, 77 (2011) 794-802.
MA
NU
[144] S.L. Warnes, S.M. Green, H.T. Michels, C.W. Keevil, Biocidal efficacy of copper alloys against pathogenic enterococci Involves degradation of genomic and plasmid DNAs, Appl Environ Microb, 76 (2010) 5390-5401. [145] W.-X. Tian, S. Yu, M. Ibrahim, A.W. Almonaofy, L. He, Q. Hui, Z. Bo, B. Li, G.-l. Xie, Copper as an antimicrobial agent against opportunistic pathogenic and multidrug
D
resistant enterobacter bacteria, Journal of Microbiology, 50 (2012) 586-593. [146] N. Cioffi, L. Torsi, N. Ditaranto, G. Tantillo, L. Ghibelli, L. Sabbatini, T. Bleve-Zacheo, M. D'Alessio, P.G. Zambonin, E. Traversa, Copper nanoparticle/polymer composites with antifungal and bacteriostatic properties, Chem Mater, 17 (2005)
AC
CE P
TE
5255-5262. [147] M. Gouda, A. Hebeish, Preparation and evaluation of CuO/Chitosan nanocomposite for antibacterial finishing cotton fabric, J Ind Text, 39 (2010) 203-214. [148] N.C. Cady, J.L. Behnke, A.D. Strickland, Copper-based nanostructured coatings on natural Cellulose: Nanocomposites exhibiting rapid and efficient inhibition of a multi-drug resistant wound pathogen, A. baumannii, and mammalian cell biocompatibility in vitro, Adv Eng Mater, 21 (2011) 2506-2514. [149] C. Gunawan, W.Y. Teoh, C.P. Marquis, R. Amal, Cytotoxic origin of copper(II) oxide nanoparticles: Comparative studies with micron-sized particles, leachate, and metal salts, ACS Nano, 5 (2011) 7214-7225. [150] P. Maniprasad, S. Santra, Novel copper (Cu) loaded core-shell silica nanoparticles with improved cu bioavailability: synthesis, characterization and study of antibacterial properties, J Biomed Nanotechnol, 8 (2012) 558-566. [151] R.R.V.a.J.B. A, Nanoparticles and their potential application as antimicrobials, science against microbial pathogens: communicating current research and technological advances, 1 (2011) 13. [152] J.T. Seil, T.J. Webster, Antibacterial effect of zinc oxide nanoparticles combined with ultrasound, Nanotechnology, 23 (2012) 495101. [153] A. Pramanik, D. Laha, D. Bhattacharya, P. Pramanik, P. Karmakar, A novel study of antibacterial activity of copper iodide nanoparticle mediated by DNA and 57
ACCEPTED MANUSCRIPT
SC R
IP
T
membrane damage, Colloids Surf B Biointerfaces, 96 (2012) 50-55. [154] C. Renz, Lichtreaktionen der Oxyde des Titans, Cers und der Erdsäuren, Helvetica Chimica Acta, 4 (1921) 961-968. [155] M.N. Chong, B. Jin, C.W.K. Chow, C. Saint, Recent developments in photocatalytic water treatment technology: A review, Water Res, 44 (2010) 2997-3027. [156] N.G. Chorianopoulos, D.S. Tsoukleris, E.Z. Panagou, P. Falaras, G.J.E. Nychas, Use of titanium dioxide (TiO2) photocatalysts as alternative means for Listeria monocytogenes biofilm disinfection in food processing, Food Microbiol, 28 (2011)
MA
NU
164-170. [157] D. Li, H. Haneda, S. Hishita, N. Ohashi, Visible-light-driven N−F−Codoped TiO2 ppotocatalysts. 2. optical characterization, photocatalysis, and potential application to air purification, Chem Mater, 17 (2005) 2596-2602. [158] L. Cermenati, P. Pichat, C. Guillard, A. Albini, Probing the TiO2 photocatalytic
D
mechanisms in water purification by use of quinoline, photo-fenton generated OH• radicals and superoxide Dismutase†, J Phys Chem B, 101 (1997) 2650-2658. [159] G. Fu, P.S. Vary, C.T. Lin, Anatase TiO2 nanocomposites for antimicrobial coatings, J Phys Chem B, 109 (2005) 8889-8898.
AC
CE P
TE
[160] Q. Li, S. Mahendra, D.Y. Lyon, L. Brunet, M.V. Liga, D. Li, P.J.J. Alvarez, Antimicrobial nanomaterials for water disinfection and microbial control: Potential applications and implications, Water Res, 42 (2008) 4591-4602. [161] R. Dastjerdi, M. Montazer, A review on the application of inorganic nano-structured materials in the modification of textiles: Focus on anti-microbial properties, Colloids Surf B Biointerfaces, 79 (2010) 5-18. [162] T. Miyagi, M. Kamei, T. Mitsuhashi, T. Ishigaki, A. Yamazaki, Charge separation at the rutile/anatase interface: a dominant factor of photocatalytic activity, Chemical Physics Lett, 390 (2004) 399-402. [163] R.R. Shah, S. Kaewgun, B.I. Lee, T.-R.J. Tzeng, The antibacterial effects of biphasic brookite-anatase titanium dioxide nanoparticles on multiple-drug-resistant Staphylococcus aureus, J Biomed Nanotechnol, 4 (2008) 339-348. [164] W.A. Daoud, J.H. Xin, Y.-H. Zhang, Surface functionalization of cellulose fibers with titanium dioxide nanoparticles and their combined bactericidal activities, Surf Sci, 599 (2005) 69-75. [165] P. Hajkova, P. Spatenka, J. Horsky, I. Horska, A. Kolouch, Photocatalytic effect of TiO2 films on viruses and bacteria, Plasma Process Polym, 4 (2007) S397-S401. [166] N.M. Mahmoodi, M. Arami, N.Y. Limaee, N.S. Tabrizi, Kinetics of heterogeneous photocatalytic degradation of reactive dyes in an immobilized TiO2 photocatalytic reactor, J Colloid Interface Sci, 295 (2006) 159-164. 58
ACCEPTED MANUSCRIPT
SC R
IP
T
[167] D.W. Sheel, L.A. Brook, I.B. Ditta, P. Evans, H.A. Foster, A. Steele, H.M. Yates, biocidal silver and silver/titania composite films grown by chemical vapour deposition, Int J Photoenergy 2008 (2008). [168] A. Erkan, U. Bakir, G. Karakas, Photocatalytic microbial inactivation over Pd doped SnO2 and TiO2 thin films, J Photoch Photobio A, 184 (2006) 313-321. [169] A. Pal, S.O. Pehkonen, L.E. Yu, M.B. Ray, Photocatalytic inactivation of gram-positive and gram-negative bacteria using fluorescent light, J Photoch Photobio A, 186 (2007) 335-341. [170] T. Matsunaga, R. Tomoda, T. Nakajima, N. Nakamura, T. Komine,
MA
NU
Continuous-sterilization system that uses photosemiconductor powders, Appl Environ Microb, 54 (1988) 1330-1333. [171] T. Saito, T. Iwase, J. Horie, T. Morioka, Mode of photocatalytic bactericidal action of powdered semiconductor TiO2 on mutans streptococci, J Photoch Photobio B, 14 (1992) 369-379.
D
[172] P. Amézaga-Madrid, R. Silveyra-Morales, L. Córdoba-Fierro, G.V. Nevárez-Moorillón, M. Miki-Yoshida, E. Orrantia-Borunda, Solı, amp, x, F.J. s, TEM evidence of ultrastructural alteration on pseudomonas aeruginosa by photocatalytic TiO2 thin films, J Photoch Photobio B, 70 (2003) 45-50.
AC
CE P
TE
[173] P. Amézaga-Madrid, G.V. Nevárez-Moorillón, E. Orrantia-Borunda, M. Miki-Yoshida, Photoinduced bactericidal activity against pseudomonas aeruginosa by TiO2 based thin films, FEMS Microbiol Rev, 211 (2002) 183-188. [174] C. Hu, J. Guo, J. Qu, X. Hu, Photocatalytic degradation of pathogenic bacteria with AgI/TiO2 under visible light irradiation, Langmuir, 23 (2007) 4982-4987. [175] J.W. Liou, H.H. Chang, Bactericidal Effects and Mechanisms of visible light-responsive titanium dioxide photocatalysts on pathogenic bacteria, Arch Immunol Ther Exp, 60 (2012) 267-275. [176] C. Wei, W.Y. Lin, Z. Zainal, N.E. Williams, K. Zhu, A.P. Kruzic, R.L. Smith, K. Rajeshwar, Bactericidal activity of TiO2 photocatalyst in aqueous media: Toward a solar-assisted water disinfection system, Environ Toxicol Chem, 28 (1994) 934-938. [177] R.R.K. Shah, Sujaree; Lee, Burtrand I.; Tzeng, Tzuen-Rong J., The antibacterial fffects of biphasic brookite-Anatase titanium dioxide nanoparticles on multiple-drug-Resistant staphylococcus aureus, J Biomed Nanotechnol, 4 (2008) 339-348. [178] S. Ciston, R.M. Lueptow, K.A. Gray, Controlling biofilm growth using reactive ceramic ultrafiltration membranes, J Membr Sci, 342 (2009) 263-268. [179] P. Dhandapani, S. Maruthamuthu, G. Rajagopal, Bio-mediated synthesis of TiO2 nanoparticles and its photocatalytic effect on aquatic biofilm, J Photoch Photobio B, 110 (2012) 43-49. 59
ACCEPTED MANUSCRIPT
SC R
IP
T
*180+ .l. Simon-Deckers, S. oo, M. Mayne- hermite, N. Herlin-Boime, N. Menguy, C.c. eynaud, B. ouget, M. Carri re, Size-, composition- and shape-dependent toxicological impact of metal oxide nanoparticles and carbon nanotubes toward bacteria, Environ Toxicol Chem, 43 (2009) 8423-8429. [181] T. Szabó, J. Németh, I. Dékány, Zinc oxide nanoparticles incorporated in ultrathin layer silicate films and their photocatalytic properties, Colloids Surf A Physicochem Eng Asp, 230 (2003) 23-35. [182] O. Yamamoto, J. Sawai, T. Sasamoto, Change in antibacterial characteristics with doping amount of ZnO in MgO–ZnO solid solution, Int J Inorg Mater 2(2000)
MA
NU
451-454. [183] M. Ansari, H. Khan, A. Khan, A. Sultan, A. Azam, Synthesis and characterization of the antibacterial potential of ZnO nanoparticles against extended-spectrum β-lactamases-producing escherichia coli and klebsiella pneumoniae isolated from a tertiary care hospital of North India, Appl Microbiol Biotechnol, 94 (2012) 467-477.
D
[184] R. Brayner, R. Ferrari-Iliou, N. Brivois, S. Djediat, M.F. Benedetti, F. Fiévet, Toxicological impact studies based on Escherichia coli bacteria in ultrafine ZnO nanoparticles colloidal medium, Nano Lett, 6 (2006) 866-870. [185] D. Sharma, J. Rajput, B.S. Kaith, M. Kaur, S. Sharma, Synthesis of ZnO
AC
CE P
TE
nanoparticles and study of their antibacterial and antifungal properties, Thin Solid Films, 519 (2010) 1224-1229. [186] S. Ikawa, K. Kitano, S. Hamaguchi, Effects of pH on bactberial inactivation in aqueous solutions due to low-temperature atmospheric pressure plasma application, Plasma Process Polym, 7 (2010) 33-42. [187] N. Jones, B. Ray, K.T. Ranjit, A.C. Manna, Antibacterial activity of ZnO nanoparticle suspensions on a broad spectrum of microorganisms, FEMS Microbiol Rev, 279 (2008) 71-76. [188] J. Sawai, T. Yoshikawa, Quantitative evaluation of antifungal activity of metallic oxide powders (MgO, CaO and ZnO) by an indirect conductimetric assay, J Appl Microbiol, 96 (2004) 803-809. [189] N. Padmavathy, R. Vijayaraghavan, Enhanced bioactivity of ZnO nanoparticles—an antimicrobial study, Sci Technol Adv Mat 9(2008) 1-7. [190] O.B. Koper, I. Lagadic, A. Volodin, K.J. Klabunde, Alkaline-Earth oxide nanoparticles obtained by aerogel methods. Characterization and rational for unexpectedly high surface chemical reactivities, Chem Mater, 9 (1997) 2468-2480. [191] O.B. Koper, J.S. Klabunde, G.L. Marchin, K.J. Klabunde, P. Stoimenov, L. Bohra, Nanoscale powders and formulations with biocidal activity toward spores and vegetative cells of bacillus species, viruses, and toxins, Curr Microbiol, 44 (2002) 49-55. 60
ACCEPTED MANUSCRIPT
SC R
IP
T
[192] J. Sawai, H. Kojima, H. Igarashi, A. Hashimoto, S. Shoji, T. Sawaki, A. Hakoda, E. Kawada, T. Kokugan, M. Shimizu, Antibacterial characteristics of magnesium oxide powder, World J Microb Biot, 16 (2000) 187-194. [193] K. Blecher, A. Nasir, A. Friedman, The growing role of nanotechnology in combating infectious disease, Virulence, 2 (2011) 395-401. [194] N. Awaya, T. Kobayashi, Self-Aligned passivation technology for copper interconnection using Copper-Aluminum alloy, Jpn J Appl Phys, 36 (1997) 112-114 [195] B.K. Li, B.E. Logan, Bacterial adhesion to glass and metal-oxide surfaces, Colloid Surface B, 36 (2004) 81-90.
MA
NU
[196] A. Mukherjee, I, Mohammed Sadiq, T.C. Prathna, N. Chandrasekaran, microbial activity of aluminium oxide nanoparticles for potential clinical applications, Science against microbial pathogens, Science against microbial pathogens: communicating current research and technological advances, (2011) 245-251. [197] V.K. Mishra, H. P. Pandey, G. Mohammad, Antioxidant properties of some
D
nanoparticle may enhance wound healing in T2DM patients., Dig J Nanomater Bios 3(2008) 159-162. [198] I.M. Sadiq, T.C. Prathna, N. Chandrasekaran, A. Mukherjee, Antimicrobial activity of aluminium oxide nanoparticles for potential clinical applications, Science
AC
CE P
TE
against microbial pathogens: communicating current research and technological advances 1(2011) 245-251. [199] I.M. Sadiq, B. Chowdhury, N. Chandrasekaran, A. Mukherjee, Antimicrobial sensitivity of Escherichia coli to alumina nanoparticles, Nanomed Nanotechnol Biol Med, 5 (2009) 282-286. [200] Z. Qiu, Y. Yu, Z. Chen, M. Jin, D. Yang, Z. Zhao, J. Wang, Z. Shen, X. Wang, D. Qian, A. Huang, B. Zhang, J.W. Li, Nanoalumina promotes the horizontal transfer of multiresistance genes mediated by plasmids across genera, Proc Natl Acad Sci U S A, 109 (2012) 4944-4949. [201] H. Xu, F. Qu, H. Xu, W. Lai, Y. Andrew Wang, Z. Aguilar, H. Wei, Role of reactive oxygen species in the antibacterial mechanism of silver nanoparticles on escherichia coli O157:H7, Biometals, 25 (2012) 45-53. [202] I. Chopra, The increasing use of silver-based products as antimicrobial agents: a useful development or a cause for concern?, J Antimicrob Chemother, 59 (2007) 587-590. [203] G. Subbiahdoss, S. Sharifi, D.W. Grijpma, S. Laurent, H.C. van der Mei, M. Mahmoudi, H.J. Busscher, Magnetic targeting of surface-modified superparamagnetic iron oxide nanoparticles yields antibacterial efficacy against biofilms of gentamicin-resistant staphylococci, Acta Biomaterialia, 8 (2012) 2047-2055. [204] R. Gokulakrishnan, S. Ravikumar, J.A. Raj, In vitro antibacterial potential of 61
ACCEPTED MANUSCRIPT
SC R
IP
T
metal oxide nanoparticles against antibiotic resistant bacterial pathogens, Asian Pacific Journal of Tropical Disease, 2 (2012) 411-413. [205] R. Hernandez-Delgadillo, D. Velasco-Arias, D. Diaz, K. Arevalo-Nino, M. Garza-Enriquez, M.A. De la Garza-Ramos, C. Cabral-Romero, Zerovalent bismuth nanoparticles inhibit streptococcus mutans growth and formation of biofilm, Int J Nanomedicine, 7 (2012) 2109-2113. [206] M.A. Syed, U. Manzoor, I. Shah, S.H. Bukhari, Antibacterial effects of tungsten nanoparticles on the escherichia coli strains isolated from catheterized urinary tract infection (UTI) cases and staphylococcus aureus, New Microbiol, 33 (2010) 329-335.
MA
NU
[207] A. Roy, S.S. Gauri, M. Bhattacharya, J. Bhattacharya, Antimicrobial activity of caO nanoparticles, J Biomed Nanotechnol, 9 (2013) 1570-1578. [208] B. Wu, R. Huang, M. Sahu, X. Feng, P. Biswas, Y.J. Tang, Bacterial responses to Cu-doped TiO2 nanoparticles, Science of The Total Environment, 408 (2010) 1755-1758.
D
[209] E. Fröhlich, E. Roblegg, Models for oral uptake of nanoparticles in consumer products, Toxicology, 291 (2012) 10-17. [210] T.J. Brunner, P. Wick, P. Manser, P. Spohn, R.N. Grass, L.K. Limbach, A. Bruinink, W.J. Stark, In vitro cytotoxicity of oxide nanoparticles: Comparison to asbestos,
AC
CE P
TE
silica, and the effect of particle solubility, Environ Toxicol Chem, 40 (2006) 4374-4381. [211] R.F. Hamilton, N. Wu, D. Porter, M. Buford, M. Wolfarth, A. Holian, Particle length-dependent titanium dioxide nanomaterials toxicity and bioactivity, Part Fibre Toxicol, 6 (2009) 35. [212] Y.S. Chen, Y.C. Hung, I. Liau, G.S. Huang, Assessment of the in vivo toxicity of gold nanoparticles, Nanoscale Res Lett, 4 (2009) 858-864. [213] H.S. Choi, W. Liu, P. Misra, E. Tanaka, J.P. Zimmer, B. Itty Ipe, M.G. Bawendi, J.V. Frangioni, Renal clearance of quantum dots, Nat Biotechnol, 25 (2007) 1165-1170. [214] F. Schrurs, D. Lison, Focusing the research efforts, Nat Nanotechnol, 7 (2012) 546-548. [215] Join the dialogue, Nat Nanotechnol, 7 (2012) 545. [216] M.D. Adhikari, S. Goswami, B.R. Panda, A. Chattopadhyay, A. Ramesh, Membrane-directed high bactericidal activity of (gold nanoparticle)-polythiophene composite for niche applications against pathogenic bacteria., Adv Healthcare Mater, 2 (4) (2013). [217] S. Shrivastava, T. Bera, A. Roy, G. Singh, P. Ramachandrarao, D. Dash, Characterization of enhanced antibacterial effects of novel silver nanoparticles, Nanotechnology, 18 (2007) 225103. *218+ . Panáček, . Kvítek, . Prucek, M. Kolář, . Večeřová, N. Pizúrová, V.K. Sharma, T.j. Nevěčná, . Zbořil, Silver colloid nanoparticles: synthesis, characterization, and 62
ACCEPTED MANUSCRIPT
SC R
IP
T
their antibacterial activity, J Phys Chem B, 110 (2006) 16248-16253. [219] D. Jain, S. Kachhwaha, R. Jain, G. Srivastava, S.L. Kothari, Novel microbial route to synthesize silver nanoparticles using spore crystal mixture of Bacillus thuringiensis, Indian J Exp Biol, 48 (2010) 1152-1156. [220] A. Nanda, M. Saravanan, Biosynthesis of silver nanoparticles from staphylococcus aureus and its antimicrobial activity against MRSA and MRSE, Nanomed Nanotechnology Biol Med, 5 (2009) 452-456. [221] M. Saravanan, A. Nanda, Extracellular synthesis of silver bionanoparticles from aspergillus clavatus and its antimicrobial activity against MRSA and MRSE, Colloids
MA
NU
Surf B Biointerfaces, 77 (2010) 214-218. [222] S.V. Otari, R.M. Patil, S.R. Waghmare, S.J. Ghosh, S.H. Pawar, A novel microbial synthesis of catalytically active Ag-alginate biohydrogel and its antimicrobial activity, Dalton Trans, 42 (2013) 9966-9975. [223] M. Doudi, N. Naghsh, M. Setorki, Comparison of the effects of silver
D
nanoparticles on pathogenic bacteria resistant to beta-lactam antibiotics (ESBLs) as a prokaryote model and wistar rats as a eukaryote model, Med Sci Monit Basic Res, 19 (2013) 103-110. [224] M. Ansari, H. Khan, A. Khan, A. Malik, A. Sultan, M. Shahid, F. Shujatullah, A.
AC
CE P
TE
Azam, Evaluation of antibacterial activity of silver nanoparticles against MSSA and MRSA on isolates from skin infections, Biol Med 3(2011) 141-146. [225] H. Lara, N. Ayala-Núñez, L. Ixtepan Turrent, C. Rodríguez Padilla, Bactericidal effect of silver nanoparticles against multidrug-resistant bacteria, World J Microbiol Biotechnol, 26 (2010) 615-621. [226] M. Eid, E. Araby, Bactericidal effect of poly(acrylamide/itaconic acid)–silver nanoparticles synthesized by gamma irradiation gainst Pseudomonas Aeruginosa, Appl Biochem Biotechnol, 171 (2013) 469-487. [227] P. Jena, S. Mohanty, R. Mallick, B. Jacob, A. Sonawane, Toxicity and antibacterial assessment of chitosan-coated silver nanoparticles on human pathogens and macrophage cells, Int J Nanomedicine, 7 (2012) 1805-1818. [228] V. Sambhy, M.M. MacBride, B.R. Peterson, A. Sen, Silver bromide nanoparticle/polymer composites: dual action tunable antimicrobial materials, J Am Chem Soc, 128 (2006) 9798-9808. [229] G. Ren, D. Hu, E.W.C. Cheng, M.A. Vargas-Reus, P. Reip, R.P. Allaker, Characterisation of copper oxide nanoparticles for antimicrobial applications, Int J Antimicrob Agents, 33 (2009) 587-590. [230] J. Lellouche, E. Kahana, S. Elias, A. Gedanken, E. Banin, Antibiofilm activity of nanosized magnesium fluoride, Biomaterials, 30 (2009) 5969-5978. [231] E.N. Taylor, K.M. Kummer, N.G. Durmus, K. Leuba, K.M. Tarquinio, T.J. Webster, 63
ACCEPTED MANUSCRIPT
SC R
IP
T
Superparamagnetic iron oxide nanoparticles (SPION) for the treatment of antibiotic-resistant biofilms, Small, 8 (2012) 3016-3027. [232] M. Mahmoudi, V. Serpooshan, Silver-Coated Engineered magnetic nanoparticles are promising for the success in the fight against antibacterial resistance Threat, ACS Nano, 6 (2012) 2656-2664. [233] R.K. Kunkalekar, M.M. Naik, S.K. Dubey, A.V. Salker, Antibacterial activity of silver-doped manganese dioxide nanoparticles on multidrug-resistant bacteria, J Chem Technol Biotechnol, 88 (2013) 873-877. [234] J.F. Hillyer, R.M. Albrecht, Gastrointestinal persorption and tissue distribution of
MA
NU
differently sized colloidal gold nanoparticles, J Pharm Sci, 90 (2001) 1927-1936. [235] X.D. Zhang, H.Y. Wu, D. Wu, Y.Y. Wang, J.H. Chang, Z.B. Zhai, A.M. Meng, P.X. Liu, L.A. Zhang, F.Y. Fan, Toxicologic effects of gold nanoparticles in vivo by different administration routes, Int J Nanomedicine, 5 (2010) 771-781. [236] X.D. Zhang, D. Wu, X. Shen, P.X. Liu, N. Yang, B. Zhao, H. Zhang, Y.M. Sun, L.A.
D
Zhang, F.Y. Fan, Size-dependent in vivo toxicity of PEG-coated gold nanoparticles, Int J Nanomed, 6 (2011) 2071-2081. [237] S. Dhar, V. Mali, S. Bodhankar, A. Shiras, B.L.V. Prasad, V. Pokharkar, Biocompatible gellan gum-reduced gold nanoparticles: cellular uptake and subacute
AC
CE P
TE
oral toxicity studies, J Appl Toxicol 31 (2011) 411-420. [238] Y.S. Kim, Kim, J.S., Cho, H.S., Rha, D.S., Kim, J.M., Park, J.D., Choi, B.S., Lim, R., Chang, H.K., Chung, Y.H., Kwon, I.H., Jeong, J., Han, B.S., Yu, I.J., Twenty-Eight-Day oral toxicity, genotoxicity, and gender-related tissue distribution of silver nanoparticles in sprague-dawley rats, Inhal Toxicol 20 (2008) 575-583. [239] E.J. Park, E. Bae, J. Yi, Y. Kim, K. Choi, S. H. Lee, J. Yoon, B. C. Lee, K. Park, Repeated-dose toxicity and inflammatory responses in mice by oral administration of silver nanoparticles, Environ Toxicol Pharmacol, 30 (2010) 162-168. [240] Z. Chen, H. Meng, G. Xing, C. Chen, Y. Zhao, G. Jia, T. Wang, H. Yuan, C. Ye, F. Zhao, Z. Chai, C. Zhu, X. Fang, B. Ma, L. Wan, Acute toxicological effects of copper nanoparticles in vivo, Toxicol Lett 163 (2006) 109-120. [241] R. Lei, C. Wu, B. Yang, H. Ma, C. Shi, Q. Wang, Q. Wang, Y. Yuan, M. Liao, Integrated metabolomic analysis of the nano-sized copper particle-induced hepatotoxicity and nephrotoxicity in rats: a rapid in vivo screening method for nanotoxicity, Toxicol Appl Pharmacol, 232 (2008) 292-301. [242] Y. Duan, N. Li, C. Liu, H. Liu, Y. Cui, H. Wang, F. Hong, Interaction between nanoparticulate anatase TiO2 and lactate dehydrogenase, Biol Trace Elem Res, 136 (2010) 302-313. [243] N. Li, Y. Duan, M. Hong, L. Zheng, M. Fei, X. Zhao, J. Wang, Y. Cui, H. Liu, J. Cai, S. Gong, H. Wang, F. Hong, Spleen injury and apoptotic pathway in mice caused by 64
ACCEPTED MANUSCRIPT
SC R
IP
T
titanium dioxide nanoparticules, Toxicol Lett, 195 (2010) 161-168. [244] Q. Bu, G. Yan, P. Deng, F. Peng, H. Lin, Y. Xu, Z. Cao, T. Zhou, A. Xue, Y. Wang, X. Cen, Y.L. Zhao, NMR-based metabonomic study of the sub-acute toxicity of titanium dioxide nanoparticles in rats after oral administration, Nanotechnology, 21 (2010) 125105. [245] J. Chen, X. Dong, J. Zhao, G. Tang, In vivo acute toxicity of titanium dioxide nanoparticles to mice after intraperitioneal injection, J Appl Toxicol, 29 (2009) 330-337. [246] B. Wang, W. Feng, M. Wang, T. Wang, Y. Gu, M. Zhu, H. Ouyang, J. Shi, F. Zhang,
MA
NU
Y. Zhao, Z. Chai, H. Wang, J. Wang, Acute toxicological impact of nano- and submicro-scaled zinc oxide powder on healthy adult mice, J Nanopart Res, 10 (2008) 263-276. [247] C.M. Sayes, K.L. Reed, D.B. Warheit, Assessing toxicity of fine and nanoparticles: comparing in vitro measurements to in vivo pulmonary toxicity
AC
CE P
TE
D
profiles, Toxicol Sci, 97 (2007) 163-180.
65
AC
CE P
TE
D
MA
NU
SC R
IP
T
ACCEPTED MANUSCRIPT
Graphical abstract
66
S0169-409X(14)00170-7 doi: 10.1016/j.addr.2014.08.004 ADR 12645
To appear in:
Advanced Drug Delivery Reviews
Received date: Revised date: Accepted date:
30 November 2013 27 June 2014 11 August 2014
Please cite this article as: Ching-Wen Chen, Chia-Yen Hsu, Syu-Ming Lai, Wei-Jhe Syu, Ting-Yi Wang, Ping-Shan Lai, Metal nanobullets for multidrug resistant bacteria and biofilms, Advanced Drug Delivery Reviews (2014), doi: 10.1016/j.addr.2014.08.004
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
Metal nanobullets for multidrug resistant bacteria and biofilms
†
SC R
Ping-Shan Lai†*
IP
T
Ching-Wen Chen†, Chia-Yen Hsu†, Syu-Ming Lai†, Wei-Jhe Syu †, Ting-Yi Wang †, and
Department of Chemistry, National Chung Hsing University, 250, Kuo Kuang
NU
Rd., Taichung 402, Taiwan
MA
*Address correspondence to: [email protected]
AC
CE P
TE
D
This review is part of the Advanced Drug Delivery Reviews theme issue on “Emergence of multidrug resistance bacteria: Important role of macromolecules as a new drug targeting microbial membranes”.
1
ACCEPTED MANUSCRIPT ABSTRACT Infectious disease was one of the major causes of mortality until now because
T
drug-resistant bacteria have arisen under broadly use and abuse of antibacterial drugs.
IP
These multidrug-resistant bacteria pose a major challenge to the effective control of
SC R
bacterial infections and this threat has prompted the development of alternative strategies to treat bacterial diseases. Recently, use of metallic nanoparticles (NPs) as antibacterial agents is one of the promising strategies against bacterial drug resistance.
NU
This review first describes mechanisms of bacterial drug resistance and then focuses
MA
on the properties and applications of metallic NPs as antibiotic agents to deal with antibiotic-sensitive and -resistant bacteria. We also provide an overview of metallic
D
NPs as bactericidal agents combating antibiotic-resistant bacteria and their potential in
AC
CE P
TE
vivo toxicology for further drug development.
Abbreviation of bacteria: A.baumannii: Acinetobacter baumannii, B. cepacia: Burkholderia cepacia, B. cereus: Bacillus cereus, C. difficile: Clostridium difficile, C. jejuni: Campylobacter jejuni, C. metallidurans: Cupriavidus metallidurans, E. aerogenes: Enterobacter aerogenes, E. agglomerans: Enterobacter agglomerans, E. amnigenus: Enterobacter amnigenus, E. cloacae: Enterobacter cloacae, E. coli: Escherichia coli, E. faecalis: Enterococcus faecalis, K. mobilis: Klebsiella mobilis, K. pneumonia: Klebsiella pneumonia, K. oxytoca: Klebsiella oxytoca, S. aureus: Staphylococcus aureus,
S. enterica: Salmonella enterica, S. epidermidis: Staphylococcus epidermidis, S.
oneidensis: Shewanella oneidensis, S. typhimurium: Salmonella TyphimuriumT, S. typhus: Scrub typhus , S. Marcescens: Serratia marcescens, S. mutans: Streptococcus mutans, S. pyogenes: Streptococcus
pyogenes,
MRSA:
methicillin-resistant
S.
aureus
(Methicillin-resistant
Staphylococcus aureus), N. meningitides: Neisseria Meningitidis, P. aeruginosa: Pseudomonas aeruginosa, P. vulgaris : Proteus vulgaris, PDRAB: pan-drug-resistant A. baumannii, VRE: Vancomycin-resistant Enterococcus, V. cholera: Vibrio cholera 2
ACCEPTED MANUSCRIPT Content 1. Introduction-----------------------------------------------------------------------------------0
T
2. Mechanisms of multidrug resistance in bacteria and biofilm formation---------0
IP
2.1 Inherent (natural) resistance ---------------------------------------------------------0
SC R
2.2 Acquired resistance---------------------------------------------------------------------0 2.3 Biofilm infections and formation----------------------------------------------------0 3.
Antimicrobial
activities
of
metal
nanoparticles
against
antibiotic
NU
resistance-----------------------------------------------------------------------------------------0
MA
3.1 Gold based nanoparticles--------------------------------------------------------------0 3.2 Silver based nanoparticles-------------------------------------------------------------0
D
3.3 Copper based nanoparticles----------------------------------------------------------0
TE
3.4 Titanium based nanoparticles--------------------------------------------------------0 3.5 Zinc oxide nanoparticles---------------------------------------------------------------0
CE P
3.6 Magnesium based nanoparticles----------------------------------------------------- 0 3.7 Aluminum based nanoparticles------------------------------------------------------ 0
AC
4. Discussion and future aspects-------------------------------------------------------------0 5. References-------------------------------------------------------------------------------------0
3
ACCEPTED MANUSCRIPT 1. Introduction Infectious disease was one of the major causes of mortality in the nineteenth
T
century. Antibiotics, which were discovered in the middle of the nineteenth century,
IP
successfully reduced the mortality caused by infectious diseases [1, 2]. Antimicrobial
SC R
agents are divided into five major classes according to their principal mechanism of action: (1) inhibitors of cell wall synthesis (e.g., Penicillin and Vancomycin) [3, 4]; (2) inhibitors of protein synthesis (aminoglycoside) [5]; (3) inhibitors of nucleic acid
NU
synthesis (fluoroquinolones for DNA synthesis inhibition and rifampin for RNA
MA
synthesis inhibition) [6, 7]; (4) anti-metabolites (trimethoprim) [8] and (5) drugs that disrupt the structure of the bacterial membrane (polymyxins and daptomycin) [9]. The
D
broad use and abuse of antibacterial drugs has led to the emergence of multidrug
TE
resistance in bacteria, which has increased at an alarming rate and is now a serious issue for clinicians treating infectious diseases. Antimicrobial resistance is very
CE P
complex and the evolutionary processes usually occur during antibiotic therapy, leading to the emergence of heritable resistance to antibiotics. Horizontal gene
AC
transfer (HGT) through bacterial conjugation, transduction, transformation or biofilm formation can spread drug resistance [10]. In fact, bacterial drug resistance has numerous negative influences upon medicine and society. Infection by drug-resistant bacteria requires the administration of high doses of antibiotics, resulting in higher drug toxicity, longer hospital stays and higher mortality [2, 11]. In the United States, antibiotic-resistant bacterial infections add $20 billion to total healthcare costs and $35 billion in costs to society [11, 12]. Thus, the effective control or elimination of drug resistance is an important goal for stopping bacterial infections [13]. Recently, metallic NPs have been reported to be versatile agents that can be used in highly sensitive diagnostic assays, thermal ablation techniques, radiotherapy and drug and gene delivery [14-16]. NPs used as drug carriers might reduce the adverse effects 4
ACCEPTED MANUSCRIPT and increase the therapeutic effects of antibiotics by improving their accumulation and pharmacokinetics. [17]. It has been also demonstrated that surface functionalized
T
metal nanoarchitectures possess antimicrobial activities and thus could be used to
IP
control infectious diseases [18, 19]. Unlike traditional organic antibacterial agents,
SC R
metal NPs have a high surface area-to-volume ratio, which enhances diffusion and imparts special mechanical, chemical, electrical, optical, magnetic, electro-optical and magneto-optical properties to the NPs, properties that are different from the bulk
NU
properties [20]. The antibacterial activity of metal NPs mainly depends on their size,
MA
stability and concentration in the growth medium. [21]. To overcome the drug resistance of bacteria, NPs reveal multifunctionalities such as improvement of
D
intracellular accumulation of antimicrobial agents [22, 23] or inhibition of biofilms
TE
formation [2, 24] with fewer adverse effects comparing to traditional antibiotics [25]. This review article consists of three parts: The first part discusses the mechanisms
CE P
of antimicrobial resistance. The second part is the discussion of metal nanoparticles as antibacterial agents against drug-sensitive and -resistant microbe. In the third part, we combating
AC
provide an overview of metallic NPs as bactericidal agents
antibiotic-resistant bacteria and their potential in vivo toxicology for further drug development.
2. Mechanisms of multidrug resistance in bacteria and biofilm formation Antibiotic misuse not only causes the potentially serious effects on human health but also induces the development of antibiotic resistance in bacteria, including the multidrug-resistant bacteria: the bacteria develop resistance to multiple antibiotics and cause life-threatening infections [26]. In addition, ubiquitous antibiotic use in animals may drive the development of drug-resistant bacteria that can be transmitted to humans [27]. For the implantation of medical devices such as artificial joints and 5
ACCEPTED MANUSCRIPT cardiac valves, bacterial adhesion on the implanted biomaterials presents a constant risk of bacterial colonization and biofilm formation [28, 29]. Bacteria use numerous
T
mechanisms of resistance to antimicrobial agents and these, for the most part, can be
SC R
IP
classified as either inherent (natural) resistance or acquired resistance [30].
2.1 Inherent (natural) resistance
Inherent (natural) resistance occurs when bacteria are intrinsically resistant to
NU
therapeutic agents. For example, bacteria that lack a transport system or target for a
MA
particular antibiotic may display drug resistance as a result. In addition, cell wall play an important resistance mechanism to reduce drug uptake, thereby preventing the
D
concentration of antibacterial agents from increasing to the toxic levels in bacteria.
TE
The wall of Gram-positive cells contains a thick layer of peptidoglycan attached to teichoic acids. Comparing to the cell wall of Gram-positive cells, Gram-negative
CE P
bacteria have complex cell wall containing thin peptidoglycan layer and outer membrane that serves as an inherent barrier to hydrophobic compounds or antibiotic
AC
penetration [31, 32], indicating less susceptibility of Gram-negative bacteria than Gram positive cells to many antibiotics.
2.2 Acquired resistance Bacteria with multidrug resistance can be transformed through the acquisition of new genetic material from other resistant organisms, a process termed horizontal gene transfer (HGT). HGT is the primary cause of bacterial antibiotic resistance, and it plays an important role in the evolution of many organisms [33-35]. Transposons in bacteria can facilitate the direct or indirect transfer and incorporation of drug resistance genes into the host’s genome or plasmids (Fig. 1). These resistance genes confer resistance to various antibiotics such as β-lactams, glycopeptides, 6
ACCEPTED MANUSCRIPT aminoglycosides, quinolones, sulfonamides, macrolides, linezolid, rifampin and tetracyclines. For example, both Gram-positive and -negative bacteria usually obtain
T
genes of tetracycline efflux pumps on plasmid or transposons, including TetA, TetB
IP
and TetK, through HGT process [36]. TetR protein can repress the expression of these
SC R
efflux genes but will be inactivated by tetracycline induction, thereby expressing the
AC
CE P
TE
D
MA
NU
tetracycline efflux pumps and causing tetracycline resistance [37] .
Fig. 1. The pathway of acquired resistance by horizontal gene transfer (HGT) in bacteria through cell-cell conjugation, viral transfer and transformation.
Multidrug resistance in bacteria can also be caused by chromosomal mutations and the regulation of resistant genes. Mechanisms of this type can be classified into 4 groups (Fig. 2). (1) Inactivation or modification of drugs. For example, bacteria may acquire genes through HGT process for specific enzymes, such as β-lactamases, that can hydrolyze the β-ring of β-lactams, thereby inactivating the killing ability of β-lactams and resulting in drug resistance [36-38]. For aminoglycosides, it has been 7
ACCEPTED MANUSCRIPT found that ACT N-acetyltransferse acetylates the amino group of aminoglycosides. APH O-phosphotransferase and ANT O-adenyltransferase can phosphorylate or hydroxyl
aminoglycoside
resistance
group gene
of
aminoglycosides,
codes
for
ACT
respectively.
T
the
N-acetyltransferse,
IP
adenylates
Some APH
SC R
O-phosphotransferase or ANT O-adenyltransferase, usually located on transposons or plasmids, can modify aminoglycoside molecules, decrease the binding affinity of aminoglycoside for the 30S ribosomal subunit and therefore reduce antibacterial
NU
activity of aminoglycoside [36, 37]. Similar resistance mechanisms involved enzyme
MA
that can chemically modify antibacterial agents, are observed to combat tetracycline, macrolides, quinolones and chloramphenicol [36, 37].
D
(2) Alteration of a target site of antibiotics. It is found that many bacteria are
TE
resistant to antibiotics through this mechanism. For example, MecA gene codes for an altered penicillin binding protein (PBP), PBP2A that present low affinity for
CE P
β-lactams, are expressed in methicillin-resistant S. aureus (MRSA), and other penicillin-resistant bacteria, resulting resistance to β-lactam antibiotics [36]. The vanA
AC
gene, conferred to glycopeptides (including vancomycin) resistance, alters the binding domain of vancomycin from D-ala-D-ala to D-ala-D-lactate in peptidoglycan precursor, thereby decreasing binding affinity of vancomycin and causing resistance [36]. Drug resistance of quinolone, macrolides, aminoglycosides, linezolid, rifampin and tetractyclines can be also referred to the alternation of antibiotic binding sites. For example, fluoroquinolone resistance in S. aureus is attributed to a mutation in the quinolone-resistance determining region (QRDR) of GrlA/GrlB (topoisomerase IV) and GyrA/GyrB (DNA gyrase), which decreases the affinity of these proteins for the drug [39-42]. Erm (erythromycin resistance methylates) gene codes for a N-methyltransferase that methylases an adenine of domain V of 23S rRNA of the 50S ribosomal subunit near the binding site of macrolides, reduce the macrolides’ binding 8
ACCEPTED MANUSCRIPT and therefore result in drug resistance [36]. Methylation of 16S rRNA of the 30S ribosomal subunit and the mutation in the rpsL gene also confer aminoglycoside
T
resistance [37]. Mutation of gene that codes for the 23S rRNA of 50S ribosomal
IP
subunit significantly reduce the binding affinity of linezolids, thereby causing
SC R
linezolid resistance [36, 37]. Rifampin binds to DNA-dependent RNA polymerase and inhibits its activity. Thus, the mutation of rpoB, which codes for β-subunit of RNA polymerase, confers resistance to rifampin [37]. For tetracycline, tetL and tetM
MA
resulting in tetracycline resistance [36].
NU
resistance gene also inhibit the binding tetracycline on 30S ribosomal subunit,
(3) Alteration of a metabolic pathway. For example, sulphonamides inhibit
D
dihydropteroate synthase in folic acid metabolism through a competitive manner with
TE
higher affinity for the enzyme than the natural substrate, p-aminobenzoic acid (PABA) [43]. PABA, an important precursor for the synthesis of folic acid and nucleic acid, is
CE P
not required in some sulfonamide-resistant bacteria to perform folic acid, thereby conferring to sulphonamides resistance [44]. Bacteria can also increase the synthesis
AC
of a competitive molecule of antibiotics to inhibit its antibacterial activity. For example, sulfonamide resistance in S. aureus or N. meningitides is enhanced by increasing the synthesis of PABA that competes with sulfonamide molecules and reduces binding of drugs on dihydropteroate synthase, thereby resulting in sulfonamide resistance [45, 46]. (4) Decreasing drug permeability or increasing the active efflux (pumping out) of drugs across the cell membrane. Efflux pumps located on the membrane are high-affinity reverse transport systems that transport antibiotics out of cells before they can reach their target sites and exert their effects on bacteria. Gram-negative bacteria P. aeruginosa have multidrug efflux pump consist of H+/drug antiporter protein in the periplasmic space and will become multidrug resistant with efflux 9
ACCEPTED MANUSCRIPT protein overexpression while a gene mutation in regulatory protein that represses gene code of those efflux protein pumps [36]. Currently, drug efflux pumps can be
T
classified into five families: the ATP-binding cassette (ABC) superfamily[47], the
IP
major facilitator superfamily (MFS) [48], the multidrug and toxic compound extrusion
SC R
(MATE) family [49], the small multidrug resistance (SMR) family [50] and the resistance-nodulation-division (RND) superfamily [51]. AcrAB/TolC is the most well understood RND efflux transporters and their expressions are repressed by acrR
NU
protein. If an acrR gene mutation occur, AcrAB/TolC is overexpressed, thereby
AC
CE P
TE
D
MA
pumping out of antibiotics and causing drug resistance of bacteria [37].
Fig. 2. Various resistant strategies of bacteria against antibacterial agents.
2.4 Biofilm formation and the mechanisms of antibiotic resistance in biofilms A bacterial biofilm is a cooperative community of unicellular organisms attached to a solid surface or encased in a hydrated matrix of polysaccharide and protein. As shown in Fig. 3, biofilms are usually formed through several steps (Fig. 3A). The 10
ACCEPTED MANUSCRIPT initial step in biofilm formation is the adherence of bacteria to a foreign body or biomaterial. The transformation from reversible to irreversible attachment is a
T
relatively rapid process, taking place within a few minutes or less [52]. Bacterial
IP
adhesion is mediated by fimbriae, pili, flagella and extracellular polymeric substance
SC R
(EPS), which form a communication bridge between bacteria and the conditioning films. The aggregation and accumulation of adherent bacteria leads to the formation of multiple cell layers as the biofilm matures. The last step is the detachment of
NU
bacteria from the biofilm into a planktonic state, which allows them to initiate a new
MA
cycle of biofilm formation [53, 54]. It has been demonstrated that gene expression in biofilm cells is different than in planktonic cells [55]. Gene regulation is dependent on
D
cell population density and is controlled by a signal molecule-driven communication
TE
system, such as the quorum sensing system [56-58]. Quorum sensing occurs in many different species and environments and is mediated by a variety of factors. For
CE P
example, Bacillus and Streptococcus produce and release virulence factors [59-61]. Biofilms can form anywhere (for example, on floor tiles or on plants), and in plants
AC
they can coexist with the plant symbiotically or cause crop disease. Biofilms can also occur on contact lenses and biomedical implants [62]. Recently, the biofilm mode of growth has been suggested to be the key factor in chronic infections. Biofilms can act as a nidus that produces periodic planktonic showers of bacteria into the bloodstream, resulting in acute infections [63]. Singh et al. found that bacteria in biofilms show a thousand-fold increase in resistance to antibiotics and are less conspicuous to the immune system [64]. Therefore, it is difficult to eliminate biofilm bacteria with antibiotics in the clinic. The hypothesis of drug resistance in biofilms was reported by Stewart et al. (Fig. 3B) [65]. (1) In biofilms, the penetration of antibiotics is slow and incomplete. To kill bacteria efficiently, an antibacterial agent must diffuse and penetrate into the bacterial 11
ACCEPTED MANUSCRIPT cells. Unfortunately, EPSs affect the diffusion of antimicrobial molecules either by chemically reacting with antibiotics or by limiting their rate of transport. Hoyle and
T
co-workers reported that dispersed P. aeruginosa were 15 times more susceptible to
IP
tobramycin than intact biofilms [66]. Gilbert et al. demonstrated that the susceptibility
SC R
of S. epidermidis to tobramycin could be decreased by biofilm formation [67]. (2) A concentration gradient of a metabolic substrate or product leads to zones of slow-growing or non-growing bacteria with less uptake of antimicrobial agents than in
NU
planktonic cells. Evans and co-workers reported that E. coli grew slowly in biofilms
MA
that were resistant to cetrimide [68]. Anwar et al. reported that older chemostat-grown P. aeruginosa biofilms were more resistant to tobramycin and piperacillin than
D
younger biofilms [69]. (3) An adaptive stress response is expressed by some bacteria.
TE
To cope with environmental fluctuations, such as temperature change, oxidative stress or DNA damage, bacteria have evolved stress responses that allow adaptation [70, 71].
CE P
Many stress responses have been studied in molecular and genetic detail in planktonic bacteria, and protective stress responses may be deployed in biofilms. Junter et al.
AC
found that agar-entrapped E. coli displayed enhanced resistance to aminoglycoside because oxygen tensions were decreased. It has been suggested that the resistance of sessile-like bacteria to aminoglycoside arises from the low uptake of antibiotics by oxygen-deprived bacteria [72]. (4) A small fraction of bacteria differentiate into a highly protected persister state that reduces the susceptibility of their biofilm to antibiotics. The persister hypothesis could explain the protection of biofilms from antimicrobial agents of very different chemistries and modes of action [73].
12
AC
CE P
TE
D
MA
NU
SC R
IP
T
ACCEPTED MANUSCRIPT
Fig. 3. The schematic of biofilm life cycle and the hypothesis of antibiotic resistant mechanism in biofilms. (A) Schematic of biofilm life cycle: (1-2) Planktonic encounter a submerged surface and attached. (3-4) The slimy extracellular polymeric substance (EPS) was produced and anchors the cells to the surface. This state is commonly referred to as irreversible attachment. (5) Once attached at the surface, cell division and recruitment of planktonic bacteria results in growth and development of the biofilm community, i.e. maturation. (6) Biofilms propagated by a type of 13
ACCEPTED MANUSCRIPT "dispersal" that releases individual cells. (B) The hypothesis of biofilm resistance
T
mechanisms.
IP
3. Antimicrobial activities of metal nanoparticles against antibiotic resistance
SC R
Multidrug resistance in bacteria leads to severe consequences in patients, such as prolonged illness and a high risk of mortality. Recently, metallic nanoparticles have been investigated as potential antibiotics that could overcome resistance. The
NU
antimicrobial activities of nanoparticles are known to be a function of the their large
MA
surface area in contact with the microorganisms, particle size, and stability, as well as the drug concentration [74-78] The potential antibiotic applications of metal NPs,
D
such as gold NPs, silver NPs, magnesium oxide NPs, copper oxide NPs, aluminum
TE
NPs, titanium dioxide NPs and zinc oxide NPs, are described below.
CE P
3.1 Gold-based nanoparticles
In the 1920s, Robert Koch observed the bacteriostatic effects of gold cyanide and
AC
used it for tubercle bacillus therapy [79]. Gold compounds are clinically used to treat many diseases, including rheumatic diseases, juvenile arthritis, palindromic rheumatism and discoid lupus erythematosus [80]. Gold NPs can reveal strong light absorption in the visible region due to the coherent oscillations of the free electrons on the particle surfaces. This phenomenon of surface plasmon resonance (SPR) in gold NPs currently has various applications [81]. For example, SPR excited optically by the attenuated total reflection can be used as biosensors [82, 83]. In addition, gold NPs with coherent oscillations boundary conditions and interband electronic transitions (d to sp) [84] exhibit optical properties and photothermal effect for destructing cells or tissues [85]. Although gold NPs alone are considered that lack antibacterial activity; however, 14
ACCEPTED MANUSCRIPT Dakshinamurthy et al. synthesized dextrose-encapsulated gold nanoparticle (dGNPs) with average diameters of 25 nm, 60 nm and 120 nm (± 5), and they found that the
T
120-nm dGNPs were the most potent antibacterial agents through disruption of
IP
bacterial cell membrane against both Gram-negative (E. coli) as well as
SC R
Gram-positive (S. epidermidis) bacteria [86]. Gold NPs can be synthesized to give them chemical or photothermal functionality; for example, they can be made into nanospheres, nanocages or nanorods with near-infrared (NIR) absorption that can
NU
destroy cancer cells and bacteria via photothermal heating [87, 88]. For example,
MA
anti-salmonella-antibody-conjugated oval-shaped gold NPs can kill S. typhimurium after NIR radiation via photothermal lysis [89]. Gold NPs can also be combined with
D
antibiotics to enhance antibacterial efficiency. Gold NPs coated with aminoglycosidic
TE
antibiotics have antibacterial effects on a range of Gram-positive and Gram-negative bacteria [90]. The antibacterial activity of gentamicin significantly increases when it
CE P
is mixed with gold nanoparticles [91]. In addition, chitosan-capped gold NPs coupled with ampicillin show twice as much antibacterial activity as free ampicillin against E.
AC
coli, S. aureus and K. mobilis [92]. Recently, the combination of photothermal gold nanoparticles with antibodies or antibiotics was shown to produce synergistic effects for antibacterial activity. Gold NPs conjugated with anti-protein A antibodies that photothermally kill S. aureus after laser irradiation [93]. Sabo-Atwood et al. conjugated polyclonal antibody against P. aeruginosa isolate (PA3) on the surface of gold nanorods and demonstrated that antibody-conjugated nanorods effectively kill pathogenic P. aeruginosa via photothermal cell lysis [94]. Vancomycin-bound gold NPs also showed successful hyperthermic killing of pathogens including Gram-positive (S. pyogenes and S. aureus), Gram-negative (E. coli UTI (urinary tract infections), E. coli O157:H7, A. baumannii) and antibiotic-resistant bacteria (Vancomycin-resistant Enterococcus 15
ACCEPTED MANUSCRIPT (VRE), methicillin-resistant S. aureus (MRSA) and pan-drug-resistant A. baumannii (PDRAB)) via NIR irradiation [95].
T
The surfaces of gold NPs are easily modified for different types of antibacterial
IP
treatments. It has been reported that photosensitizers conjugated with gold nanorods
photo-hyperthermia
[88].
Gold
nanorods
SC R
killed MRSA by photodynamic antimicrobial chemotherapy (PACT) and NIR conjugated
with
a
hydrophilic
photosensitizer, toluidine blue O, were used for antimicrobial photodynamic therapy
NU
and hyperthermia via synergistic combination effects to kill MRSA [96]. The
MA
antimicrobial activity of the antibiotic vancomycin against vancomycin-resistant enterococci (VRE) was enhanced by coating with gold NPs [97]. Ampicillin-capped
D
gold NPs also show potential antibacterial activity against multidrug resistant bacteria,
TE
including MRSA, P. aeruginosa, E. aerogenes and E. coli K-12 substrain DH5-alpha [98].
CE P
The detailed mechanisms that allow gold NPs to inhibit bacterial growth are still under investigation. Cui et al. found that the antibacterial action of gold NPs depends
AC
on two events: decreasing the intracellular ATP levels by alternation of membrane potential or inhibition of ATP synthase activity and inhibition of the tRNA-binding subunit of the ribosome. The action of gold NPs does not include a reactive oxygen species (ROS) mechanism, although ROS damage is the cause of cellular death induced by some bactericidal antibiotics and nanomaterials [99]. Liang et al. demonstrated that gold NPs with different surface modifications but the same shape and particle size exhibited different inhibitory effects. Poly-allylamine hydrochloride (PAH)-capped gold NPs caused cell lysis, whereas citrate-capped gold NPs did not [100]. Gold NPs coated with a second generation β-lactam antibiotic, Cefaclor, have efficient antimicrobial activity on both Gram-positive (S. aureus) and Gram-negative bacteria (E. coli), in contrast to Cefacior or gold NPs treatment alone [18]. When used 16
ACCEPTED MANUSCRIPT against Gram-positive bacteria, cefaclor first reacted with the outer peptidoglycan layer and increased the membrane porosity. Subsequently, gold NPs penetrated into
T
the bacteria and prevented DNA from unwinding, stopping transcription. This
IP
phenomenon provided the antibacterial activity of the cefaclor-capped gold NPs.
SC R
When used against Gram-negative bacteria, gold NPs first penetrate through the membrane, and cefaclor reacts with the inner peptidoglycan layer, generating holes in the membrane. The DNA binding of gold NPs subsequently occurs, resulting in
NU
slower antibacterial activity compared to the fast activity observed in Gram-negative
MA
bacteria [18, 90].
D
Silver-based nanoparticles
TE
Silver ions and silver-based compounds are highly toxic to microorganisms [101-103], and they have been widely used for biomedical applications such as the
CE P
treatment of burns, wounds and infections [104-106]. In general, silver is applied in its nitrate form to induce an antimicrobial effect. Recently, nanosized silver particles
AC
with greatly expanded surface areas were shown to have excellent antimicrobial properties [107, 108], and such particles can now be used as disinfect filters and coating materials against bacteria [109, 110]. Mecking et al. showed that hybrids of silver NPs with amphiphilic hyperbranched macromolecules showed effective antimicrobial properties when used as surface-coating agents [111]. For wound healing, silver NPs provide antibacterial ability that significantly reduces scar formation in a dose-dependent manner by decreasing inflammation through cytokine modulation [112]. Recently, silver NPs and coatings of other silver species have been used on implants and medical devices to impede the formation of biofilms and decrease the incidence of infections [113, 114]. Silver NPs also have antibacterial activity against a 17
ACCEPTED MANUSCRIPT wide of bacteria including drug resistant microbes. A study by Lara et al. showed the potential bactericidal silver NPs against multidrug resistant P. aeruginosa,
T
ampicillin-resistant E. coli O157:H7 and erythromycin-resistant S. pyogenes [115].
IP
Dolman et al. also showed that the silver-containing Hydrofiber® dressing and
SC R
nanocrystalline silver-containing dressing are effective agents against Gram-negative bacteria, including P. aeruginosa, K. pneumonia and E. coli; Gram-positive bacteria, including E. faecalis, S. aureus and antibiotic resistant bacteria, such as MRSA, VRE
NU
and S. Marcescens. These dressings on biomaterials also work by preventing biofilm
MA
formation [116]. It is also shown that silver NPs can act not only as antibacterial agents but also as antiviral and antifungal agents [117, 118]. Silver NPs immobilized
D
on the surface of nanoscale silicate platelets (AgNP/NSPs) also have strong
TE
antibacterial activity against MRSA and silver-resistant E. coli. These particles exert their effect through the generation of ROS at the contact surfaces [119]. Therefore,
CE P
nanoscale silver crystals can act as effective broad spectrum bactericidal agents against both drug-sensitive and -resistant microbes.
AC
Silver NPs have great antibacterial activity through multiple mechanisms. Morones et al. suggested that silver NPs first attach to the surface of the cell membrane, disturb its function, penetrate the bacterium and release silver ions that result in efficient antibacterial activity against Gram-negative bacteria (E. coli, V. cholera, P. aeruginosa and S. typhus) [120]. Salopek-Sondi and Dash demonstrated that silver NPs can anchor to the bacterial cell wall, penetrate the cell wall and finally lead to cell death [121, 122]. It is noted that silver NPs with smaller volume and larger surface area have increased ability to penetrate through the cell wall and cell membranes into bacterial cells [123]. The generation of free radicals by silver NPs is also considered to be a possible mechanism of antibacterial activity. Kim et al. reported that free radicals produced by silver NPs can cause cell membrane damage and increase 18
ACCEPTED MANUSCRIPT membrane porosity, leading to cell death [124]. Intracellular silver ions released from silver NPs can interact with phosphorus moieties in DNA to inactivate DNA
T
replication. Silver ions can also react with sulfur-containing proteins to increase the
IP
ROS level and inhibit respiratory enzymes, resulting in cell death [120, 125, 126]. The
SC R
hypothesis is that silver ions act as soft acids to facilitate the formation of complexes with sulfur- or phosphorus-containing ligands, which act as soft bases [120, 127]. Chueh et al. showed that the action of silver NPs evokes inflammatory responses in
NU
host cells due to ROS production, which induces cell apoptosis and increases the
MA
transcription of pro-inflammatory cytokines via activation of the c-Jun N-terminal
D
kinase pathway [128].
TE
Copper-based nanoparticles
Copper, one of the essential trace elements, is vital to organisms and crucial for the
CE P
functioning of organs and metabolic processes; however, in low or excessive amounts, copper can have deleterious effects [129-131]. It is demonstrated that copper can act
AC
as an electron donor/acceptor by alternating between the redox states copper (I) and copper (II) in some enzymes, thereby increasing toxicity to the bacteria [132, 133]. An alternative route of copper ion induced toxicity is proposed to involve the displacement of iron from iron-sulfur clusters [134]. However, some bacteria such as C. difficile may protect themselves from the toxic effects of copper or copper ions while contacting with copper surface. One of possible mechanisms regarding copper resistance of bacteria is due to the formation of endospores [135]. The antibacterial abilities of copper have been widely tested in human pathogens, including MRSA, C. difficile, E. coli and P. aeruginosa [136]. A remarkable decrease in viable bacteria was observed after incubation with metallic copper; thus, the main 19
ACCEPTED MANUSCRIPT mechanism of antibacterial activity for copper is suggested to be contact-mediated killing. For example, the B. cepacia complex consists of 17 closely related bacterial
T
species that are difficult to eradicate, and it was observed that the contact time of
IP
copper on the B. cepacia complex is an important factor for antibacterial activity [133,
SC R
137]. A study of Faudez et al. also showed similar results for S. enterica and C. jejuni [138]. The contact interface is also important for copper-mediated antibacterial activity. In a “dry” test, a very small amount of liquid is dropped on the metallic
NU
surface with a cotton swab. It evaporates within seconds, thereby allowing direct cell
MA
contact with the metal [131, 139]. The minimal required time for complete B. seminalis death was 1 minute on dry copper surfaces, but it was 14 hours on moist
D
copper surfaces [137]. The color change of copper from dark brown to pale blue via
TE
oxidation-reduction reactions can be used as a simple indicator for copper (II) ion release in a copper contact assay [138].
CE P
By the paper disc assay, copper powder has been shown to be an efficient antibacterial agent against drug-resistant Enterobacter species [140]. Noyce et al. investigated copper’s antimicrobial effects on different strains of MRSA and reported
AC
the complete killing of 107 cfu inoculums of MRSA (NTCT 10442) on copper [141]. Steindl et al. also reported that MRSA ST398, NDM-1-producing K. pneumonia and CTX-M-producing E. coli were sensitive to copper, with less than 103 cfu remaining after 2 hours [142]. Copper also exerts strong antibacterial effects through the bacterial intracellular influx of copper ions in the B. cepacia complex [137]. Bacterial contact killing by copper is preceded by a sequence of specific actions: cell membrane damage, copper influx into the cells, oxidative damage and DNA damage [143]. The targeting of DNA by copper leads to rapid DNA fragmentation and cell death [133, 144]. After exposure to copper, fragmented or tailed DNA can be observed in the B. cepacia complex and Enterobacter [137, 145]. Copper-based NPs 20
ACCEPTED MANUSCRIPT also show potential for the direct or indirect killing of multidrug-resistant bacteria. Through the combination of other materials with copper nanoparticles, it is possible to
T
create versatile antibacterial agents that work on drug-sensitive and drug-resistant
IP
bacteria [146-150]. Strickand et al. showed that a copper-cotton nanocomposite was
SC R
efficient at killing multidrug-resistant bacteria not only by direct contact killing but also by enhancing the release of copper ions [148]. Copper NPs can be capped with a cationic polymer such as chitosan to enhance their interaction with the negatively
NU
charged cell envelope [151]. Compared to Gram-negative bacteria such as E. coli.,
MA
Gram-positive bacteria (e.g., S. aureus) are more sensitive to copper nanoparticles [74, 75, 152]. Amal et al. investigated the source of toxicity of copper oxide NPs by
D
examining their leaching characteristics and speciation, and the results showed that
TE
the rates of cellular ROS generation in E. coli are different for different sizes of NPs [149]. ROS most likely formed on the surfaces of copper NPs in the presence of
CE P
amine functional groups from various biological molecules [153]. Thus, copper-based NPs serve as potential antibacterial agents that can kill drug-resistant bacteria, and
AC
their antibacterial mechanism may need to be evaluated in greater detail.
Titanium (IV) oxide-based nanoparticles The applications and properties of titanium (IV) oxide (TiO2) have been known for over 90 years [154]. TiO2 NPs as catalyst can generate electron–hole pairs with photo-excitation, initiate cascade oxidative-reductive reactions at the TiO2 surface and therefore produce ROS for further reactions [155]. For microbial killing, TiO2 NPs with light irradiation significantly inhibit the growth of bacteria through the peroxidation of lipids in membranes, DNA damage or oxidized nucleotides, and oxidation of amino acids or breakage of protein catalytic centers via photocatalysis [156]. The self-cleaning ability of TiO2, which can be used in environmental 21
ACCEPTED MANUSCRIPT purification to remove contaminants in the air and water, is well known [157, 158]. TiO2 NPs with photocatalytic disinfection abilities can be used as antibacterial agents
T
for antibiotic-sensitive and antibiotic-resistant bacteria [155, 159-161].
IP
The structures of TiO2 can be classified into three crystalline forms: anatase, rutile
SC R
and brookite. TiO2 NPs in the anatase form show the highest photocatalytic efficiency. Recently, it was shown that a mixture of these crystalline structures (79% anatase and 21% rutile phases or brookite-anatase which consist of 45% anatase, 2% rutile, and
NU
53% brookite) also has good photocatalytic activity [162, 163]. When TiO2 NPs are
MA
irradiated with wavelengths below approximately 385 nm, the absorption of a photon with sufficient energy (equal to or higher than its band gap, ~3.2 eV) transfers
D
electrons from the valence band (O 2p) to the conduction band (Ti 3d), leaving a
TE
positively charged hole in the valence band. These electron/hole pairs can react with oxygen or water to form superoxide (O2·) or hydroxyl radicals (OH·) that has a ability
CE P
to decompose organic species into carbon dioxide and water [155]. Thus, TiO2 NPs can be applied to kill bacteria, to eliminate viruses, and even to clean up some odor
AC
molecules [164-166]. When final process of photocatalysis was completed, various highly active oxygen species had been generated. Thus, these highly active species would be reacting with organic matters such as odor molecules, bacteria and virus then causing these reactants degradation or destruction. It was reported that TiO2 NPs can kill both Gram-negative and Gram-positive bacteria by photocatalysis, although Gram-negative bacteria are particularly sensitive [167-169]. This difference between Gram-negative and Gram-positive bacteria may be due to their different cell wall structures. Gram-negative bacteria have a triple-layer cell wall structure with a thin peptidoglycan layer in the inner and outer membranes, whereas Gram-positive bacteria have only one thicker peptidoglycan layer that facilitates the absorbance of reactive radicals, thereby preventing cell damage from radical attack [169]. TiO2 NPs 22
ACCEPTED MANUSCRIPT have bactericidal effects through multiple mechanisms. Matsunaga et al. showed that the TiO2 has the potential against bacteria via receiving an electron from intracellular
T
coenzyme A (CoA) after the photocatalysis of TiO2, followed by the formation of
IP
dimeric CoA and the subsequent inhibition of respiration [170]. T. Saito et al.
SC R
demonstrated that the photochemical reaction caused by TiO2 NPs disrupted the cell membrane and the cell wall to cause cell death [171]. These membrane structure change phenomena can be observed by scanning electron microscopy or transmission
NU
electron microscopy [172, 173]. The production of aldehydes, ketones, and carboxylic
MA
acids is also considered to be evidence of membrane degradation or peroxidation in E. coli cells treated with TiO2 NPs [174]. The internal components of lysed bacteria leak
D
from the cells through the damaged area, resulting in cell death via photocatalysis
TE
[175]. Thus, TiO2 NPs with suitable irradiation provide a promising and feasible approach for the disinfection of pathogenic bacteria, thereby facilitating the
CE P
prevention of infectious diseases.
The antibacterial activity of TiO2 NPs is also dependent on particle size, light dose
AC
and the wavelength of irradiation [176]. Shah et al. showed that 10-15 nm TiO2 NPs with highly efficient membrane damage against multidrug-resistant S. aureus via efficient photocatalysis [177]. In addition, TiO2 NPs can reduce the adhesion of bacteria and inhibit the formation of biofilms [178, 179]. However, TiO2 NPs did not show good bactericidal efficiency against some types of drug-resistant bacteria (e.g., C. metallidurans CH34) that have a remarkable capacity to resist membrane damage caused by ROS via the overexpression of protective components and membrane restoration elements [180]. Thus, TiO2 NPs combined with other agents with different antibacterial mechanisms may provide a potential bactericidal strategy to use against drug-resistant bacteria. 23
ACCEPTED MANUSCRIPT Zinc oxide nanoparticles Zinc oxide NPs also show bactericidal activity via multiple mechanisms including
T
photo-oxidation and photocatalysis [181]. The antibacterial effects of zinc oxide
IP
depends on the volume of NPs. Sasamoto et al. showed zinc oxide NPs (10-50 nm)
SC R
exhibited better antimicrobial properties than bulk zinc oxide (2 μm) [182]. The cell penetration of smaller size of zinc oxide NPs can be enhanced by ultrasound. A study of Thomas et al. demonstrated that the combination of zinc oxide NPs with ultrasound
NU
enhanced the antibacterial effect on S. aureus by generating more hydrogen peroxide
MA
[152]. In addition, ultrasonic treatment can physically facilitate the dissociation of cell membranes, thereby increasing the penetration of zinc oxide NPs into cells.
D
For combating with drug resistant bacteria, zinc oxide NPs with a diameter of ~19 nm
TE
can be used against strains of Enterobacteriaceae, especially E. coli and K. pneumoniae, that exhibit extended spectrum β-lactamase (ESBL)-mediated resistance
CE P
to third-generation cephalosporins [183]. The activity of these particles may depend on disruption of the cell membrane [184] and therefore produce greater leakage of
AC
cytoplasmic contents while they are in contact with the bacteria [185]. Another antibacterial mechanism of zinc oxide NPs is the increase in intracellular ROS levels (such as OH·, H2O2, and O2-·), which is activated by UV and visible light irradiation. The OH· and O2-· cannot penetrate the cell membrane because of their charges or reactivity [186] and are likely to remain on the cell surface, whereas H2O2 can penetrate into bacterial cells, thereby inducing cell death during infection [187-189].
Magnesium-based nanoparticles Magnesium oxide NPs and magnesium halogen-containing NPs are two major magnesium-based antibacterial agents to combat microbes. Magnesium oxide NPs reveal strong interactions with negatively charged bacteria and spores because of their 24
ACCEPTED MANUSCRIPT large surface area, the abundance of crystal defects and positively charged particles [190, 191]. Active oxygen formation, such as superoxide O2-, on the surface of
T
magnesium oxide is considered to be one of antibacterial mechanisms of magnesium
IP
oxide[182, 192]. Magnesium oxide NPs exhibit activity against bacteria, spores and
SC R
viruses after adsorption of halogen molecules. These metal halogene complexes show bactericidal effects through the following possible mechanisms: formation of ROS that may cause lipid peroxidation of microbial cell envelope, alteration of membrane
NU
potential or inhibition of certain enzymes of bacteria [193], MgF2 NPs that can inhibit
MA
growth and biofilm formation of E. coli and S. aureus is a typical of magnesium
D
halogene complexes[193].
TE
Aluminum-based nanoparticles
Aluminum-based nanoparticles are thermodynamically stable across a wide range
CE P
of temperatures, and they are easy to protect while aluminum is exposed and in contact with atmospheric oxygen. A self-passivating oxide layer of alumina forms on
AC
the particles rapidly, which provides a protective covering that stops further oxidation [194]. Aggregations of particles are affected by pH and salinity, variations of which may lead to different toxicity assessments. At near-neutral pH, the prepared alumina NPs have a positive surface charge that improves the electrostatic interactions between the negatively charged surface of E. coli cells and the alumina particles, resulting in the adhesion of alumina NPs on the surfaces of the bacteria [195, 196]. The common antimicrobial effects of metal-based NPs work through ROS generation, which disrupts cell walls and leads to cell death. Interestingly, alumina NPs may serve as radical scavengers [197]. Mukherjee reported that alumina NPs mildly inhibited E. coli at high concentrations of up to 1,000 μg/mL, and they showed that this can cause distortion in bacterial cells [198, 199]. However, aluminum oxide NPs might actually 25
ACCEPTED MANUSCRIPT increase the likelihood of developing drug resistance. Qiu et al. demonstrated that aluminum oxide NP increases the risk of horizontal transfer of antibiotic resistance
T
genes by up to 200 times (in the case of transfer from E. coli to Salmonella by
IP
conjugation) [200]. The oxidative damage caused by aluminum oxide NPs may
SC R
trigger an increase in gene expression to promote conjugation.
Discussion and future directions
NU
In the past few decades, multidrug resistance has emerged in many frequently
MA
encountered pathogenic bacteria, sometimes culminating in resistance to all licensed antibacterial agents [13]. Thus, the emergence of antibiotic- resistant bacteria is
D
recognized as a crucial challenge facing public health. NPs offer a new strategy for
TE
killing drug resistant bacteria. To combat the resistant bacteria, NPs can efficiently administer antibiotics by improving their accumulation and pharmacokinetics and
CE P
reducing their adverse effects [17]. In addition, metallic NPs as antibacterial agents provide several advantages in treatment of the drug resistant bacteria. First, NPs with
AC
high surface area to volume ratio not only reveal new mechanical, chemical, electrical, optical, magnetic, electro-optical, and magneto-optical properties against bacteria [20] but also attack a broad range of targets in the bacteria, thereby increasing antimicrobial efficacy in drug sensitive or resistant bacteria. Second, metallic NPs act as versatile antibacterial agents that can significantly reduce the risk of metallic NPs-mediated bacterial resistance compared with classic antibiotics-induced resistance [201, 202]. Table 1 summarizes recently published work on antibacterial treatments using metallic and metal oxide NPs against drug-resistant bacteria and biofilm formation. Several metallic NPs, such as superparamagnetic iron oxide (SPIO)-based NPs, Bi-NPs, CaO-NPs, W-NPs that show antibacterial abilities are also included [203-207]. Most metallic NPs reveal antibacterial activity through multiple 26
ACCEPTED MANUSCRIPT mechanisms that can be explained why metal based NPs can combat drug-resistant bacteria, including the inhibition of biofilm formation (Fig. 4). Attachment of metallic
T
NPs on cell surface first cause cell membrane damage or permeability change, thereby
IP
enhancing penetration of NPs into bacterial cells. Metallic NPs with external
SC R
stimulation, such as UV, visible or NIR light irradiation, facilitate penetration of particles. Intracellular ROS generation or metal ion release from metallic NPs usually cause the damage of biomolecules (enzyme, DNA, ribosomal subunit, mRNA),
NU
thereby inactivating its functions and enhancing cell death. Blocking of efflux pump is
MA
also a specific mechanism of metallic NPs against drug resistant bacteria. Here we show many literatures regarding metallic NPs against bacteria; however, some
D
bacteria may defense themselves against metallic NPs. For example, S. oneidensis
TE
MR-1 (-) has excellent resistant against copper ion released from copper-doped TiO2 because this strain produce EPSs under NP stress [208]. Thus, package of multiple
CE P
antibacterial agents in one metallic nanoparticle might a potential nanobullet against multiple drug resistance of microbes.
AC
However, there are still several disadvantages of metallic NPs as antibacterial agents. The major one is the potential nanotoxicity of metallic NPs after administration. To facilitate the use of metallic NPs as antibacterial agents for human health, the toxicity of NP exposure in animals and humans must be studied before large-scale production [209]. Table 2 summarizes the in vivo toxicity of metal NPs. The toxicities of NPs are affected by three factors: (1) the solubility, charge and shape of the NPs causes different levels of toxicity in animals [210]. (2) The modification of NPs or their surfaces can also alter their toxicity. For example, morphological changes of nanomaterials may cause them to be unrecognizable to phagocytic cells, lead to more toxicity [211]. (3) The size of NPs also influences their toxicity. Small NPs that show efficient antibacterial activity may easily penetrate the skin, lungs, and brain and 27
ACCEPTED MANUSCRIPT cause adverse effects. In addition, metallic NPs, after administration, might be accumulated mainly in the organs, including the spleen, liver and kidney, which may
T
result in different degrees of injury [212]. Frangioni et al. proposed three criteria for
IP
distinguishing a nanoparticle have a clinical potential candidate: (1) a final
SC R
hydrodynamic size≦5.5 nm to permit complete elimination from the body and/or (2) the formulation without toxic components and/or (3) the formulation compositions have the ability of biodegrading into clearable components [213]. Thus, the metallic
NU
NPs and their formulations need to satisfy these criteria to push them into clinical trial.
MA
Moreover, the potential harmful and toxicities of metallic NPs have to be studied via systemic and consistency assessment methods. The experimental platforms based on
D
metallic NPs and biological species are difficult to generalize in individual studies.
TE
Thus, the correlation between physicochemical properties of metallic NPs and bacteria killing ability or nanotoxicology is not easy to be clearly defined [214]. To
CE P
unravel systematically nanotoxicology of NPs, nanotoxicological community has discussed the general guidelines and established common parameters regarding
AC
nanotoxicology for further nano-related studies that can efficiently accelerate the using of nanoproducts for clinical applications [215].”
28
AC
CE P
TE D
MA N
US
CR
IP
T
ACCEPTED MANUSCRIPT
Fig. 4. Multiple mechanisms of metallic NPs against drug-resistant bacteria
29
ACCEPTED MANUSCRIPT
Table 1. Various metallic NPs against pathogenic bacteria and their formation of biofilm metallic NPs
properties of metal NPs
potential of metallic NPs
Au-PAA-TBO nanorod
Toluidine blue O (TBO) conjugation
Au nanorods: length: 35 nm, width: 9.3 nm
Bacteria
Antibiotic resistance type
S. aureus (+)
US MA N
(HR-TEM)
TE D
n–Au-NPs
CE P
1.8–2.0 nm
AC
conjugate
IgG-conjugated anti-PA3 primary Au nanorods antibodies conjugation
Au nanorods: length: 68 nm, width: 18 nm
P. aerugnosa (-)
Mechanisms of
Remarks
Refs
antibacterial action
Gold based NPs Methicillin-resistant
(TEM), ~13 mV
TBO –tioproni
Applied dosage
T
Size and zeta
0.9-1.8×109 Au nanorods, 633 nm laser for 1 min
Photodynamic inactivation and hyperthermia
Combination of PACT and hyperthermia
(PACT) and 808 nm laser for 25 min (hyperthermia)
effect
TBO(4
Photodynamic
led to an enhanced antimicrobial effect (~32 % additive effect) Increased
μM)–tiopronin–Au-N Ps: ~18.4 μg/mL, PDT: 632.8 nm laser, 2.1-10.5 J
inactivation, killing bacteria in light dose dependent manner
IP
Surface physical
CR
Composition of
[88]
[96]
extinction coefficient of the conjugate compare to free TBO result in
four-folds reduction in MBC Cipromycin, Au nanorod: Antibody Covalently [94] imipenem, unrevealed, NIR recognition, NIR coupled and gentamicin- light: 785 nm, 80 treatment result in antibody-nano 30
ACCEPTED resistantMANUSCRIPT mW, 5 minutes
(TEM)
irreparable bacterial
rod complex cell is much more
nm P. aeruginosa (-)
Biofilm formation
IP
100–300 (DLS)
CR
Au-NPs–polyth Polythiophene iophene (PTh) blended
stable under physiological conditions Au-NPs-PTh: 30-112 Au-NPs-PTh Without [216] μM (antibiofilm could pervade cytotoxicity activity assay) through the on HT-29 extracellular cells even at
T
surface damage
US
composite
TE D
MA N
matrix and then an access to the Au-NPs-PTh structured of of 112 μM bacteria microcolonies embedded in the
Ag-NPs
Bare silver
10–15 nm (TEM), weak
AC
CE P
biofilm result in cellular membrane damage
E. coli (-)
Silver based NPs Ampicillin- resistant
positive charges S. typhus (-)
Multi-drug resistant
31
Ag-NPs: 5-25 μg/mL (agar diffusion
Anchor to the cell Dose membrane, dependent,
method)
perforations formation in the membrane result in cell lysis
gram-negative bacteria are more susceptible, black debris was observed
[217]
ACCEPTED MANUSCRIPT
which was proposed a
CR
IP
T
defense mechanism to deplete locally Ag concentration Best [218] antimicrobial
DLS results: Glucose:
S. epidermidis Methicillin-resistant (+)
saccharides as reducing agent)
~44-453 nm
S. aureus (+)
Lactose:
Vancomycin-resistant
evaluated respectively, Ag: 0.84-54 μg/mL (MIC and MBC assay)
K. pneumoniae ESBLs (-)
AC
CE P
~35-286 nm
E. faecium (+)
MA N
Maltose: ~25-290 nm
Smallest Ag Proposed colloid-NPs size were mechanism:
TE D
Galactose: ~50-343 nm
US
Ag colloid-NPs Not shown (various
Biosynthetic Ag-NPs
Not shown
10-20 nm (TEM), 15 nm (XRD)
E. coli (-), P. Multi-drug resistant aeruginos (-) and S. aureus (+)
32
Ag-NPs: 50 ppm (disc diffusion method)
attach to the cell membrane, disturb its permeability and respiration, penetrate into the
effect: 25 nm-size (maltose), Lowest antimicrobial effect: 50
bacteria, Agcolloid-NPs and its releasing silver ions react with bacterial DNA
nm-size (galactose) and self-aggregati on was observed in hours
Ag-NPs attach onto surface bacteria membrane disturbing
may the of cell
Biosynthesis [219] of Ag-NPs from B. thuringiensis spore crystal the mixture
ACCEPTED MANUSCRIPT
160-180 nm (AFM)
S. aureus (+) Methicillin-resistant and S. epidermidis (+)
Ag-NPs: 2 μg in 20 μL (well diffusion method)
T
Not shown
function Citing reference: inhibition of bacterial cell wall synthesis (MRSA)
Amino acid 550–650 nm residues and (AFM) protein which are present in the
Ag-NPs: 5-15 μL (disc and well diffusion method)
Unrevealed
AC
CE P
bio-synthesis procedure
S. aureus (+) Methicillin-resistant and S. epidermidis (+)
TE D
Biosynthetic Ag-NPs
MA N
US
CR
IP
Biosynthetic Ag-NPs
permeability and respiration
Ag–NPs immobilized in alginate beads (Ag–Alg biohydrogel)
Not shown
< 15 nm in the
S. aureus (+),
Erythromycin-
polymer (TEM), 4.9 nm (XRD)
B. cereus (+), E. resistant faecalis (+), E. coli (-), P. aeruginosa (-), K. pneumonia (-), and S. 33
Ag–Alg biohydrogel:
Cell surface
2 mg (agar diffusion method)
damage and lost of the chain integrity
Biosynthesis [220] of Ag-NPs from S. aureus, Gram-positive bacteria were susceptible to Ag-NPs Biosynthesis [221] of Ag-NPs from A. clavatus, non zone of inhibition for both MRSA and MRSE in 5 μL of Ag-NPs Biosynthesis [222] of Ag-NPs from actinobacteria Rhodococcus NCIM 2891, which was
ACCEPTED MANUSCRIPT typhimurium (-)
immobilized in alginate,
Tehran Company)
E. coli (-), A. 186 clinical samples baumannii (-), S. marcescens (-), E. cloacae (-), K. oxytoca (-), E. aerogenes, C.
membrane, cell membrane destruction, removal of intracellular materials and causing bacteria
(Wistar rat) was observed on 3 days after intraperitoneal injection (50 ppm) but liver
freundii (-) and P. vulgaris (-)
death
damage returned on 8 days after the injection Reduction in [224] bacterial
CE P
TE D
K. pneumoniae ESBLs producing (-), P. microorganisms aeroginosa, (-), which isolated from
Pars
Ag-NPs: 12.5-500 ppm (disc diffusion method)
Commercial Ag-NPs
Gram negative bacteria Citing reference: Severe [223] Ag-NPs penetrate irritation in into bacterial cell liver cells
Not shown 4 nm (purchased from Nano Nasb
AC
Commercial Ag-NPs
MA N
US
CR
IP
T
Gram positive bacteria were found to have some resistance to Ag-NPs more than that of
Not shown (procured
5-10 nm
S. aureus (+)
Methicillin-resistant
from 34
Ag-NPs: ~1.56-200 μg/mL, MIC: 12.5
Unrevealed
ACCEPTED MANUSCRIPT μg/mL, MBC: 25
Nanoparticle Biochem, Inc.)
μg/mL
Methicillin-resistant
E. coli (-)
Ampicillin-resistant
Ag-NPs: 30-100 mM (MIC and MBC assay)
IP
T
S. aureus (+)
CR
Not shown 100 nm (Sigma–Aldrich Co., LLC.)
Multi-drug resistant
Ag-NPs concentration Suggested Ag-NPs mechanism: resistant destabilizing and strains were disrupting the grown at outer membrane, various denaturing the 30s ribosome subunit, suppressing ATP production, inhibiting
Ag-NPs concentration: MRSA (100 mM), drug-suscepti ble S. aureus
respiratory enzymes, binding and dimerizing RNA and DNA
(200 mM), multi-drug resistant P. aeruginosa (75 mM), ampicillin-resi stant E. coli
AC
CE P
TE D
P. aeruginosa (-)
MA N
US
Commercial Ag-NPs
growth with increasing
Poly(acrylami de/itaconic acid)-Ag-NPs (P(AAm/IA)Ag-NPs)
Bare silver binding with nitrogen and oxygen moieties of copolymer
42.11-50.6 nm (20-70 kGy gamma irradiation, XRD)
S. aureus (+)
Methicillin-resistant
P(AAm/IA)-Ag-NP s: 5-200 μg/mL (MIC and MBC assay)
35
Attached to the surface of bacterial cell wall, permeated the cell
[225]
(75 mM) Polymerizatio [226] n of monomer by gamma irradiation, multi-drug
membrane and entered into the
resistant P. aeruginosa
aeruginosa (-)
cell interior, cell membrane damage result in changing the cell permeability, leak the intracellular contents by cell
was most susceptible to
Predominantly P. aeruginosa two sizes of (-) and S. CS-Ag-NPs: 55 aureus (+) and 278 nm (DLS), 51.1 mV
Biofilm formation
MA N
Chitosan coating
TE D
Chitosan coated Ag-NPs
US
CR
IP
T
ACCEPTED MANUSCRIPT K. pneumoniae Multi-drug resistant (-), and P.
CE P
cause by the interaction of silver ions with phosphorous- and sulfur-containing compounds
AC Ag-based-NPs coated carboxymethyl ated cotton
Bare metal or Not shown metallic oxide
A. Baumannii(-)
0.5-5 ppm (antibiofilm activity assay)
disruption Cell integrity destruction, DNA fragmentation, irreversible damage may
Multi-drug resistant
36
~12 μg Ag in bacteria Contact-killing liquid culture mechanism (high surface area to volume ratio)
P(AAm/IA)Ag-NPs
Cytotoxicity in macrophages was not significantly
[227]
affected in the presence of 3 ppm but dropped drastically at the nanoparticle concentration of 10 ppm Proved to be fatal to NIH3T3 cell
[148]
Ag-NPs/NSP
Bare silver which immobilized on the surface NSP
of
ANP-NPs: 6.66±2.7nm (TEM),
MANUSCRIPT S. aureusACCEPTED (+) Meticillin-resistant Ag-NPs/NSP: 64.9 Conducted in E. μM, 129.8 μM, 324.5 coil: the
NSP
average
US
CR
IP
T
dimension of 80×80×1~100× 100×1 nm3
μM and 648.9 μM conentation of (MIC assay) Ag-NPs on the NSP is predominant factor on biocidal effect, bacteria cell membrane
MA N S. aureus (+)
methicillin-resistant
N-alkylation of poly(4-vinylpyr idine)
0.4-20 mg composite in 0.5 mL of mammalian fluid (serum, saliva, or blood)
37
[119]
activity of Ag-NPs/NSP on silver-resistan t E.coli by bypassing Ag+ mechanism
surfaces adhesion, integrity of the inner membrane breakage, ROS generation, nutrient uptake
TE D TEM results: AgBr/NPVP: Ag/Br ratio in compostie/%
CE P
NPVP blended
AC
AgBr-NPs/NP VP composite
The antibacterial
impeded, ATP synthesis decreased Bacterial membrane disruption by the ampiphilic NPVP, leached silver ion from composite result in bacteria
[228]
1:1/21%: 17±9 nm
P. (-)
ACCEPTED aeruginosa BiofilmMANUSCRIPT formation 3×150 μL of 5 wt % death and 1:1 AgBr /21% inhibition biofilm NPVP composite formation coated surface
1:2/21%: 9±4 nm
IP
T
1:1/43%: 71±11 nm
CR
1:2/43%: 10±4 nm A. Baumannii (-)
Multi-drug resistant
MA N
Bare metal or < 5 nm metallic oxide (FESEM)
~30 μg Cu in bacteria Contact-killing liquid culture mechanism (high surface area to volume ratio) partially responsible for
CuO-NPs
Bare copper (II) 22.4-94.8 nm oxide (TEM)
AC
CE P
TE D
Cu-based-NPs carboxymethyl ated cotton
US
Copper based NPs
S. aureus (+)
Meticillin-resistant
1000 μg/mL (MBC assay)
S. aureus (+)
Epidemic
250-1000μg/mL
meticillin-resistant
(MBC assay)
Titanium based NPs 38
Without [148] cytotoxicity on NIH 3T3 cell
bacteria killing, interanalization of some degree of Cu Precise Gram-negativ mechanism of e strains action of showed a CuO-NPs is ongoing investigations
greater susceptibility to CuO-NPs combined with Ag-NPs
[229]
Nanofabritech)
dilution method) with UV light irradiation (365 nm, 370 μ W/cm2)
~ 40 nm
21% rutile)
MA N
E.oli (-) and K. pneumoniae (-)
TE D
~19 nm (SEM)
CE P
Not shown
Zinc oxide NPs ESBLs
AC
ZnO
Activation of TIO2 upon UV
Smaller size brookite
irradiation which produce radicals and anions to destruct organic substances
nanoparticles which promote nanoparticles to contact the bacteria cell membrane
Citing reference: more reactivity due to the nanoscale of
MIC value for E. coli and K. pneumonia: 500 μg/mL,
particle, adhesion on the bacteria membrane result in the damage of cell wall, production of ROS,
completely inhibit the bacterial growth at 1000 μg/mL
[163]
US
Not shown (purchased from Degussa Co.)
MANUSCRIPT S. aureusACCEPTED (+) Multi-drug resistant TiO2-NPs: 0.001-100 mg/mL (broth
T
45% anatase, 2% rutile, and 53% brookite) Commercial TiO2-NPs (P25-NPs, 79% anatase and
~10-15 nm
IP
Not shown (Supplied by
CR
TiO2-NPs (Br200-NPs,
NPs: 0-1000 μg/mL (colony forming assay)
penetration and internalization of NPs into bacteria Magnesium based NPs
39
[183]
Not shown
< 30 nm (TEM)
ACCEPTED MANUSCRIPT P. aeruginosa Antibiotic resistant NPs: 10-60 μg/mL (-), S. (MIC and MBC
Proposed mechanism:
None of NPs shown
pneumoniae(+) and S. aureus (+)
inhibition the production of β-lactamasae enzyme or the blocking of efflux pump pathway by MgO-NPs
sensitivity against the Streptococcus sp., CeO2-NPs showed no activity to all test pathogens
assay)
MgF2-NPs
Bare magnesium fluoride
MA N
US
CR
IP
T
MgO-NPs
E. coli (-), S. (HR-TEM), ~30 aureus (+)
Biofilm formation
20–25 nm
TE D
nm (XRD)
in MIC and MBC assay MgF2-NPs : ~0.023-1.5 mg/mL (antibiofilm activity assay)
Association on the cell surface, cell wall damage, penetrate into
CE P
cell, decrease in membrane potential, promotes the peroxidation of the lipids in the membrane
AC MgF2-NPs coated glass (microscope glass slides)
~25 nm (AFM)
MgF2-NPs completely coated on glass slid surface
40
[204]
Restricted bacterial colonization on the MgF2-NP coated glass for three days
[230]
ACCEPTED MANUSCRIPT Other metallic or metal oxide NPs
0.5 mV 14.9 ± 1.8 nm (DLS), -7.71 ±0.9 mV 19.93±1.31 nm (DLS), 8.65 ±
PEGylated SPIO-NPs
PEG750
Dimercaptosuc cinic acid
DMSA chelated
(DMSA) chelated SPIO-NPs
0.24 nm (XRD), 9.92 ± 3.14 nm (TEM), –35.5 mV Iron chelated via 23.32 ±1.17 nm DMSA (DLS), –34.0 mV
FeCl3 coated SPIO-NPs
ZnCl2 coated SPIO-NPs
ROS generation,
An external
(+)
biofilm formation
electrostatic interaction between metal NPs and bacteria
magnetic field applied to increase the penetration of biofilm
T
mg/mL (growth inhibition on adhering bacteria), CES-grafted SPIO-NPs: 0.35 mg/mL (magnetic effect during and
IP CR US
(DLS), 43.7 ± 1.7 mV APTES-grafted APTES 17.8 ± 2.6 nm SPIO-NPs (DLS), 32.6 ± 0.3 mV CES-grafted Carboxyethylsilan 13.8 ± 2.1 nm SPIO-NPs etriol (DLS), -15.4 ±
Gentamicin- resistant, Each SPIO-NPs: 0.35
MA N
SPIO-NPs
S. Epidermidis
S. aureus (+)
Biofilm formation
TE D
13.7 ± 2.1 nm
CE P
Bare iron oxide
AC
Bare
Zinc chelated via 19.67±0.72 nm DMSA (DLS), –40.1 mV
41
after biofilm formation)
[203]
No bacterial toxicity
Fe: 3.7-370 μg/mL (growth inhibition
Binding to the bacterial surface
Biofilm recovery at
and antibiofilm activity assay for each SPIO-NPs) Fe: 3.7-370 μg/mL, FeCl3 contain up to 0.002% Zn as
(SasG receptor) and blocking the formation of biofilm, penetrate into bacteria, releasing metal irons
higher zinc concentration, magnetic mediating biofilm penetration and separation
contamination Fe: 3.7-370 μg/mL, Zn: ~0.412-41.2μg/mL
intracellularly, decreasing intracellular bacillithiol,
of flocculated bacteria
[231]
~40nm (TEM)
S. epidermidis (+) and S. aureus (+)
Biofilm formation
Not shown
14–24 nm (TEM), 16 nm (XRD)
P. aeruginosa (+)
Biofilm formation
Al2O3-NPs
Not shown
< 50 nm (TEM)
P. aeruginosa (-), S.
Antibiotic resistant
Fe3O4-NPs
9-11 nm (TEM)
ZrO2-NPs
< 100 nm (TEM) < 25 nm (TEM)
pneumoniae(+) and S. aureus (+)
Not shown
< 40 nm (XRD)
TE D
2-4 mM (antibiofilm activity assay)
NPs: 10-60 μg/mL (MIC and MBC
reducing bacterial growth Upregulation of ROS production, deep penetration of biofilm using an external magnetic field
assay)
Methicillin-resistant
42
NPs: 0-500 μg (disc diffusion method)
[207]
[204]
sensitivity against the Streptococcus sp., CeO2-NPs showed no activity to all test pathogens
CE P
S. aureus (+)
No traces of [232] silver-coated SPIO NPs in mitochondria of cells (HepG2)
Cell lysis or disruption of cell wall structure Unrevealed None of NPs shown
AC
CeO2-NPs
MA N
CaO-NPs
Ag-doped MnO2
μg/mL Total metal ions: 80 μg/mL (bacteria growth inhibition)
CR
Ag-Au coated SPIO-NPs
Ag: ~1.126-112.57
T
Bare silver
mV ~20nm (TEM)
ACCEPTED MANUSCRIPT Fe: 3.7-370 μg/mL,
IP
Ag coated SPIO-NPs
Silver chelated 193.72±6.15 nm via DMSA (DLS), –43.2
US
AgNO3 coated SPIO-NPs
Formation of pits in the cell walls
in MIC and MBC assay There were no [233] zone of
ACCEPTED MANUSCRIPT P. aeruginosa Multidrug-resistant (-)
or breakdown of the cellularity
inhibition shown in the
W-NPs: 1500μg/mL (MIC assay)
Proposed mechanism:
presence of MnO2, Ni0.95Ag0.05O2 and Ce0.95Ag0.05O2 PVP as a stabilizer and PVP alone did not show any antibacterial activity.
2 mM (antibiofilm
inhibition of the microbial processes on the cell surface and within the cell Approximately 69% of cells were inactivated by the Bi-NPs which was not sufficient to form a biofilm
Bi-NPs for bacterial growth inhibition was 0.5 mM
Bare tungsten
8.1±2.8 nm (TEM)
E. coli (-) and S. Sulphamethoxazole aureus (+) and Cefotaxime-
Bi-NPs
Bare bismuth
3.3 ± 0.97 nm
S. mutans (+)
Biofilm formation
activity assay)
AC
CE P
(TEM)
TE D
MA N
resistant
US
W-NPs
CR
IP
T
(Mn0.95Ag0.05O 2)
MIC of
[206]
[205]
PACT: photodynamic antimicrobial chemotherapy, PDT: photodynamic therapy, NIR: near-infrared radiation, SPIO: superparamagnetic iron oxide, TEM: transmission electron microscopy, XRD: X-ray diffraction, MIC: Minimum inhibitory concentration, MBC: Minimum Bactericidal Concentration, ESBLs: extended-spectrum β-lactamases, NSP: nanoscale silicate platelets, PAA: polyacrylic acid, APTES: 3-Aminopropyltriethoxysilane, CES: carboxyethylsilanetriol sodium, PEG750: Polyethylene glycol 750, PVP: poly-(N-vinyl-2-pyrrolidone), NPVP: poly(4-vinylpyridine)-co-poly(4-vinyl-N-hexylpyridinium bromide)
43
ACCEPTED MANUSCRIPT
Au (4, 10, 28, and 58 nm)
137.5-2200 μg/kg
MA N
High concentration Au NPs decreased body
intraperitoneal and tail
for 14–28 days
weight, red blood cells, hematocrit. Oral
TE D
Oral administration,
AC
Intraperitoneal injection
[234]
[235]
administration decreased in body weight,
CE P 30, and 60 nm)
5, 10,
References
liver, spleen, lung, brain. Larger NPs were accumulated in the gastrointestinal tract.
vein injection
Au NPs (PEG-coated,
Physiology and histopathology changes
200 μg/kg for 7 Smaller NPs were accumulated in kidney,
Oral administration
days
Au (13.5nm)
IP
Does /duration
CR
Administration route
US
Mental NPs/size
T
Table 2. Toxicities of metal NPs assessed in vivo.
spleen index, and red blood cells. No change at low concentration.
4 mg/kg for 28
5 nm and 10 nm Au NPs mainly
days
accumulated in liver and decreased white blood cells. 30 nm Au NPs accumulated in spleen. 60 nm Au NPs caused liver and kidney damage.
44
[236]
75 , 150 and 300
No effect in blood chemistry, body weight
ppm for 28 days
T
Oral administration
[237]
and organ histology.
Ag NPs (22 nm, 42 nm, 71 nm
Oral administration
Oral administration
The concentration at 125 mg/ml caused liver
mg/kg for 90 days
damage.
1 mg/kg for 14
Smaller size Ag NPs were distributed to
days
brain, lung, liver, kidney, and testis.
TE D
and 323nm)
30, 125 and 500
MA N
Ag (56nm)
US
CR
Au NPs (14nm)
IP
ACCEPTED MANUSCRIPT
Cu (25nm)
Oral administration
[239]
Larger size Ag NPs were not detected in
CE P
Oral administration
AC
Cu (23.5nm)
[238]
tissues.
108 and 1,080 mg/kg
kidney, liver, and spleen severe injury
[240]
50 and 200 mg/kg
Liver and kidney damage
[241]
62.5, 125 and 250
Body weight decreased and liver damage,
[242]
mg/kg for 14 days
pathological blood count at ≥125 mg/kg
for 5 days TiO2 (5nm)
Intraperitoneal injection
45
ACCEPTED MANUSCRIPT
5, 50 and 150
Spleen injury
T
Intraperitoneal injection
Oral administration
160, 400 and 1000
US
TiO2 NPs (＜50nm)
CR
mg/kg for 45 days
The concentration at 1g/kg caused liver
[244]
damage, disturbance of energy and amino acid metabolism.
324, 648, 972,
Spleen, liver and kidney damage, thrombosis [245]
injection
1296, 1944 and
detected in the pulmonary vascular system in
2592mg/ kg for 24,
high dose concentration.
TE D
Intraperitioneal
CE P
TiO2 (80, 110 and 100 nm)
MA N
mg/kg for 15 days
[243]
IP
TiO2 (6 to 7nm)
48 hours, 7 and 14
ZnO (20nm and 120nM)
ZnO (50, 70 and <1,000 nm)
AC
days
Oral administration
Instillation
1, 2, 3, 4 and 5
Zn was mainly accumulated in the bone,
g/kg for 14 days
kidney and pancreas.
1 and 5mg/kg for
Reversible inflammatory response
24hours, 1week, 1 and 3 months
46
[246]
[247]
ACCEPTED MANUSCRIPT Acknowledgements This
work
was
founded
by
National
Health
Research
Institutes
IP
T
(NHRI-EX102-10114EC) and National Science Council.
SC R
References [1] M.L. Cohen, Changing patterns of infectious disease, Nature, 406 (2000) 762-767. [2] A.J. Huh, Y.J. Kwon, "Nanoantibiotics": a new paradigm for treating infectious
MA
NU
diseases using nanomaterials in the antibiotics resistant era, J Control Release, 156 (2011) 128-145. [3] P.J. Highton, D.G. Hobbs, Penicillin and cell wall synthesis: a study of Bacillus cereus by electron microscopy, J Bacteriol, 109 (1972) 1181-1190. [4] D.L. Goldman, Vancomycin, Pediatrics in Review, 16 (1995) 357-358. [5] H.W. Taber, J.P. Mueller, P.F. Miller, A.S. Arrow, Bacterial uptake of aminoglycoside
D
antibiotics, Microbiol Rev, 51 (1987) 439-457. [6] X.S. Pan, L.M. Fisher, Streptococcus pneumoniae DNA gyrase and topoisomerase IV: overexpression, purification, and differential inhibition by fluoroquinolones,
AC
CE P
TE
Antimicrob Agents Ch, 43 (1999) 1129-1136. [7] E. Battaner, B.V. Kumar, Rifampin: inhibition of ribonucleic acid synthesis after potentiation by amphotericin B in Saccharomyces cerevisiae, Antimicrob Agents Ch, 5 (1974) 371-376. [8] E.P. Quinlivan, McPartlin, J., Donald G,. Scott, J., Mechanism of the antimicrobial drug trimethoprim revisited, The FASEB Journal, 14 (2000) 2519-2524. [9] S.S. Richter, D.E. Kealey, C.T. Murray, K.P. Heilmann, S.L. Coffman, G.V. Doern, The in vitro activity of daptomycin against staphylococcus aureus and enterococcus species, J Antimicrob Chemother, 52 (2003) 123-127. [10] W. Witte, International dissemination of antibiotic resistant strains of bacterial pathogens, Infection, Genetics and Evolution, 4 (2004) 187-191. [11] M.A. Riley, S.M. Robinson, C.M. Roy, M. Dennis, V. Liu, R.L. Dorit, Resistance is futile: the bacteriocin model for addressing the antibiotic resistance challenge, Biochem Soc Trans, 40 (2012) 1438-1442. [12] C. Baker-Austin, M.S. Wright, R. Stepanauskas, J.V. McArthur, Co-selection of antibiotic and metal resistance, Trends Microbiol, 14 (2006) 176-182. [13] D.A. Tadesse, S. Zhao, E. Tong, S. Ayers, A. Singh, M.J. Bartholomew, P.F. McDermott, Antimicrobial drug resistance in Escherichia coli from humans and food animals, United States, 1950-2002, Emerg Infect Dis, 18 (2012) 741-749. [14] P. Baptista, E. Pereira, P. Eaton, G. Doria, A. Miranda, I. Gomes, P. Quaresma, R. Franco, Gold nanoparticles for the development of clinical diagnosis methods, Anal 47
ACCEPTED MANUSCRIPT
SC R
IP
T
Bioanal Chem, 391 (2008) 943-950. [15] L.R. Hirsch, R.J. Stafford, J.A. Bankson, S.R. Sershen, B. Rivera, R.E. Price, J.D. Hazle, N.J. Halas, J.L. West, Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance, Proc Natl Acad Sci U S A, 100 (2003) 13549-13554. [16] G. Han, P. Ghosh, V. Rotello, Multi-Functional gold nanoparticles for drug delivery, in: W.W. Chan (Ed.) Bio-Applications of Nanoparticles, Springer New York, 2007, pp. 48-56. [17] R.P. Allaker, G. Ren, Potential impact of nanotechnology on the control of
MA
NU
infectious diseases, R Soc Trop Med Hyg, 102 (2008) 1-2. [18] A. Rai, A. Prabhune, C.C. Perry, Antibiotic mediated synthesis of gold nanoparticles with potent antimicrobial activity and their application in antimicrobial coatings, J Materials Chemistry, 20 (2010) 6789-6798. [19] C.M. Goodman, C.D. McCusker, T. Yilmaz, V.M. Rotello, Toxicity of gold
D
nanoparticles functionalized with cationic and anionic side chains, Bioconjugate Chem, 15 (2004) 897-900. [20] G.M. Whitesides, Nanoscience, nanotechnology, and chemistry, Small, 1 (2005) 172-179.
AC
CE P
TE
[21] K.R. Raghupathi, R.T. Koodali, A.C. Manna, Size-dependent bacterial growth inhibition and mechanism of antibacterial activity of zinc oxide nanoparticles, Langmuir, 27 (2011) 4020-4028. [22] L. Zhang, D. Pornpattananangku, C.M. Hu, C.M. Huang, Development of nanoparticles for antimicrobial drug delivery, Curr Med Chem, 17 (2010) 585-594. [23] C.H. Huang, Chen, C.H., Dissaya, P., Li, Z., Chan, M., Hsieh, M.F., Zhang, L., Eradication of drug resistant Staphylococcus aureus by liposomal oleic acids, Biomaterials, 32 (2011) 214-221. [24] M.J. Hajipour, K.M. Fromm, A. Akbar Ashkarran, D. Jimenez de Aberasturi, I.R.d. Larramendi, T. Rojo, V. Serpooshan, W.J. Parak, M. Mahmoudi, Antibacterial properties of nanoparticles, Trends Biotechnol, 30 (2012) 499-511. [25] J.G. Leid, A.J. Ditto, A. Knapp, P.N. Shah, B.D. Wright, R. Blust, L. Christensen, C.B. Clemons, J.P. Wilber, G.W. Young, A.G. Kang, M.J. Panzner, C.L. Cannon, Y.H. Yun, W.J. Youngs, N.M. Seckinger, E.K. Cope, In vitro antimicrobial studies of silver carbene complexes: activity of free and nanoparticle carbene formulations against clinical isolates of pathogenic bacteria, J Antimicrob Chemother, 67 (2012) 138-148. [26] S.T. Harrison JW, The beginning of the end of the antibiotic era? Part II. Proposed solutions to antibiotic abuse, Quintessence Int, 29 (1998) 223-229. [27] D.L. Smith, A.D. Harris, J.A. Johnson, E.K. Silbergeld, J.G. Morris, Jr., Animal antibiotic use has an early but important impact on the emergence of antibiotic 48
ACCEPTED MANUSCRIPT
SC R
IP
T
resistance in human commensal bacteria, Proc Natl Acad Sci U S A, 99 (2002) 6434-6439. [28] P.J. James, I.A. Butcher, E.R. Gardner, D.L. Hamblen, Methicillin-resistant Staphylococcus epidermidis in infection of hip arthroplasties, J Bone Joint Surg Br, 76 (1994) 725-727. [29] P.Y. Litzler, L. Benard, N. Barbier-Frebourg, S. Vilain, T. Jouenne, E. Beucher, C. Bunel, J.F. Lemeland, J.P. Bessou, Biofilm formation on pyrolytic carbon heart valves: influence of surface free energy, roughness, and bacterial species, J Thorac Cardiovasc Surg, 134 (2007) 1025-1032.
MA
NU
[30] A. Percival, W. Brumfitt, J. De Louvois, The role of penicillinase in determining natural and acquired resistance of Gram-negative bacteria to penicillins, J Gen Microbiol, 32 (1963) 77-89. [31] H. Yoneyama, R. Katsumata, Antibiotic resistance in bacteria and its future for novel antibiotic development, Biosci Biotech Bioch, 70 (2006) 1060-1075.
D
[32] G.D. Wright, Bacterial resistance to antibiotics: enzymatic degradation and modification, Adv Drug Deliv Rev, 57 (2005) 1451-1470. [33] K. Ochiai, T. Yamanaka, K. Kimura, O. Sawada, Inheritance of drug resistance (and its transfer) between Shigella strains and between Shigella and E. coli strains (in
AC
CE P
TE
Japanese), Hihon Iji Shimpor, 1861 (1959) 34. [34] E.V. Koonin, K.S. Makarova, L. Aravind, Horizontal gene transfer in prokaryotes: quantification and classification, Annu Rev Microbiol, 55 (2001) 709-742. [35] K.M. Nielsen, Barriers to horizontal gene transfer by natural transformation in soil bacteria, APMIS Suppl, 84 (1998) 77-84. [36] K. Poole, Mechanisms of bacterial biocide and antibiotic resistance, J Appl Microbiol, 92 (2002) 55s-64s. [37] R. Jayaraman, Antibiotic resistance: an overview of mechanisms and a paradigm shift, Curr Sci India, 96 (2009) 1475-1484. [38] E.P. Abraham, E. Chain, An enzyme from bacteria able to destroy penicillin. 1940, Rev Infect Dis, 10 (1988) 677-678. [39] G.W. Kaatz, S.M. Seo, C.A. Ruble, Efflux-mediated fluoroquinolone resistance in Staphylococcus aureus, Antimicrob Agents Ch, 37 (1993) 1086-1094. [40] L. Ferrero, B. Cameron, J. Crouzet, Analysis of gyrA and grlA mutations in stepwise-selected ciprofloxacin-resistant mutants of Staphylococcus aureus, Antimicrob Agents Ch, 39 (1995) 1554-1558. [41] E.Y. Ng, M. Trucksis, D.C. Hooper, Quinolone resistance mutations in topoisomerase IV: relationship to the flqA locus and genetic evidence that topoisomerase IV is the primary target and DNA gyrase is the secondary target of fluoroquinolones in Staphylococcus aureus, Antimicrob Agents Ch, 40 (1996) 49
ACCEPTED MANUSCRIPT
SC R
IP
T
1881-1888. [42] M. Takahata, M. Yonezawa, S. Kurose, N. Futakuchi, N. Matsubara, Y. Watanabe, H. Narita, Mutations in the gyrA and grlA genes of quinolone-resistant clinical isolates of methicillin-resistant Staphylococcus aureus, J Antimicrob Chemother, 38 (1996) 543-546. [43] K. Bockstael, A. Van Aerschot, Antimicrobial resistance in bacteria, Cent Eur J Med, 4 (2009) 141-155. [44] W.W. Spink, L.D. Wright, J.J. Vivino, H.R. Skeggs, Para-aminobenzoic acid production by Staphylococci, J Exp Med, 79 (1944) 331-339.
MA
NU
[45] D.H. Deck, L.G., Winston, Sulfonamides, trimethoprim, & quinolones, in:B. Katzung, S. Masters, A. Trevor (Eds.), in: Basic and clinical pharmacology,12th ed, 2012, pp. 831–838. [46] P. Iliades, S.R. Meshnick, I.G. Macreadie, Dihydropteroate synthase mutations in Pneumocystis jiroveci can affect sulfamethoxazole resistance in a saccharomyces
D
cerevisiae model, Antimicrob Agents Ch, 48 (2004) 2617-2623. [47] J. Lubelski, W.N. Konings, A.J. Driessen, Distribution and physiology of ABC-type transporters contributing to multidrug resistance in bacteria, Microbiol Mol Biol Rev, 71 (2007) 463-476.
AC
CE P
TE
[48] S.S. Pao, I.T. Paulsen, M.H. Saier, Jr., Major facilitator superfamily, Microbiol Mol Biol Rev, 62 (1998) 1-34. [49] T. Kuroda, T. Tsuchiya, Multidrug efflux transporters in the MATE family, Biochim Biophys Acta, 1794 (2009) 763-768. [50] D.L. Jack, N.M. Yang, M.H. Saier, Jr., The drug/metabolite transporter superfamily, Eur J Biochem, 268 (2001) 3620-3639. [51] X.Z. Li, H. Nikaido, Efflux-mediated drug resistance in bacteria, Drugs, 64 (2004) 159-204. [52] J. Palmer, S. Flint, J. Brooks, Bacterial cell attachment, the beginning of a biofilm, J Ind Microbiol Biotechnol, 34 (2007) 577-588. [53] R.M. Donlan, Biofilm formation: a clinically relevant microbiological process, Clin Infect Dis, 33 (2001) 1387-1392. [54] C.R. Arciola, D. Campoccia, P. Speziale, L. Montanaro, J.W. Costerton, Biofilm formation in Staphylococcus implant infections. A review of molecular mechanisms and implications for biofilm-resistant materials, Biomaterials, 33 (2012) 5967-5982. [55] M. Hentzer, L. Eberl, M. Givskov, Transcriptome analysis of pseudomonas aeruginosa biofilm development: anaerobic respiration and iron limitation, Biofilms, 2 (2005) 37-61. [56] T.R. Garrett, M. Bhakoo, Z. Zhang, Characterisation of bacterial adhesion and removal in a flow chamber by micromanipulation measurements, Biotechnol Lett, 30 50
ACCEPTED MANUSCRIPT
SC R
IP
T
(2008) 427-433. [57] W.M. Dunne, Jr., Bacterial adhesion: seen any good biofilms lately?, Clin Microbiol Rev, 15 (2002) 155-166. [58] M.B. Miller, B.L. Bassler, Quorum sensing in bacteria, Annu Rev Microbiol, 55 (2001) 165-199. [59] F. Harrison, Microbial ecology of the cystic fibrosis lung, Microbiology, 153 (2007) 917-923. [60] F.C. Petersen, L. Tao, A.A. Scheie, DNA binding-uptake system: a link between cell-to-cell communication and biofilm formation, J Bacteriol, 187 (2005) 4392-4400.
MA
NU
[61] S. Park, P.M. Wolanin, E.A. Yuzbashyan, H. Lin, N.C. Darnton, J.B. Stock, P. Silberzan, R. Austin, Influence of topology on bacterial social interaction, Proc Natl Acad Sci U S A, 100 (2003) 13910-13915. [62] G. O'Toole, H.B. Kaplan, R. Kolter, Biofilm formation as microbial development, Annu Rev Microbiol, 54 (2000) 49-79.
D
[63] J.W. Costerton, P.S. Stewart, E.P. Greenberg, Bacterial biofilms: a common cause of persistent infections, Science, 284 (1999) 1318-1322. [64] M.R. Parsek, P.K. Singh, Bacterial biofilms: An emerging link to disease pathogenesis, Annu Rev Microbiol, 57 (2003) 677-701.
AC
CE P
TE
[65] P.S. Stewart, Mechanisms of antibiotic resistance in bacterial biofilms, Int J Med Microbiol, 292 (2002) 107-113. [66] B.D. Hoyle, C.K. Wong, J.W. Costerton, Disparate efficacy of tobramycin on Ca(2+)-, Mg(2+)-, and HEPES-treated pseudomonas aeruginosa biofilms, Can J Microbiol, 38 (1992) 1214-1218. [67] I.G. Duguid, E. Evans, M.R. Brown, P. Gilbert, Effect of biofilm culture upon the susceptibility of staphylococcus epidermidis to tobramycin, J Antimicrob Chemother, 30 (1992) 803-810. [68] D.J. Evans, D.G. Allison, M.R.W. Brown, P. Gilbert, Effect of growth-rate on resistance of gram-negative biofilms to cetrimide, J Antimicrob Chemother, 26 (1990) 473-478. [69] H. Anwar, J.L. Strap, K. Chen, J.W. Costerton, Dynamic interactions of biofilms of mucoid pseudomonas aeruginosa with tobramycin and piperacillin, Antimicrob Agents Ch, 36 (1992) 1208-1214. [70] B. Poolman, E. Glaasker, Regulation of compatible solute accumulation in bacteria, Mol Microbiol, 29 (1998) 397-407. [71] G. Storz, J.A. Imlayt, Oxidative stress, Curr Opin Microbiol, 2 (1999) 188-194. [72] O. Tresse, T. Jouenne, G.-A. Junter, The role of oxygen limitation in the resistance of agar-entrapped, sessile-like Escherichia coli to aminoglycoside and β-lactam antibiotics, J Antimicrob Chemother, 36 (1995) 521-526. 51
ACCEPTED MANUSCRIPT
SC R
IP
T
[73] A.L. Spoering, K. Lewis, Biofilms and planktonic cells of pseudomonas aeruginosa have similar resistance to killing by antimicrobials, J Bacteriol, 183 (2001) 6746-6751. [74] K.Y. Yoon, J. Hoon Byeon, J.H. Park, J. Hwang, Susceptibility constants of escherichia coli and bacillus subtilis to silver and copper nanoparticles, Sci Total Environ, 373 (2007) 572-575. [75] J.P. Ruparelia, A.K. Chatterjee, S.P. Duttagupta, S. Mukherji, Strain specificity in antimicrobial activity of silver and copper nanoparticles, Acta Biomater, 4 (2008) 707-716. [76] P.K. Stoimenov, R.L. Klinger, G.L. Marchin, K.J. Klabunde, Metal oxide
MA
NU
nanoparticles as bactericidal agents, Langmuir, 18 (2002) 6679-6686. [77] K.R. Raghupathi, R.T. Koodali, A.C. Manna, Size-dependent bacterial growth inhibition and mechanism of antibacterial activity of zinc oxide nanoparticles, Langmuir, 27 (2011) 4020-4028. [78] R.P. Feynman, There's plenty of room at the bottom, Science, 254 (1991)
D
1300-1301. [79] I.C. Shaw, Gold-based therapeutic agents, Chem Rev, 99 (1999) 2589-2600. [80] A.E. Finkelstein, D.T. Walz, V. Batista, M. Mizraji, F. Roisman, A. Misher, Auranofin. New oral gold compound for treatment of rheumatoid arthritis, Ann
AC
CE P
TE
Rheum Dis, 35 (1976) 251-257. [81] M.A. El-Sayed, Some interesting properties of metals confined in time and nanometer space of different shapes, Acc Chem Res, 34 (2001) 257-264. [82] E. Hutter, J.H. Fendler, D. Roy, Surface plasmon resonance studies of gold and silver nanoparticles linked to gold and silver substrates by 2-aminoethanethiol and 1,6-hexanedithiol, J Phys Chem B, 105 (2001) 11159-11168. [83] J. Wang, G. Zhu, M. You, E. Song, M.I. Shukoor, K. Zhang, M.B. Altman, Y. Chen, Z. Zhu, C.Z. Huang, W. Tan, Assembly of aptamer switch probes and photosensitizer on gold nanorods for targeted photothermal and photodynamic cancer therapy, ACS Nano, 6 (2012) 5070-5077. [84] T.A. El-Brolossy, T. Abdallah, M.B. Mohamed, S. Abdallah, K. Easawi, S. Negm, H. Talaat, Shape and size dependence of the surface plasmon resonance of gold nanoparticles studied by photoacoustic technique, Eur Phys J Spec Top, 153 (2008) 361-364. [85] J. Lin, S. Wang, P. Huang, Z. Wang, S. Chen, G. Niu, W. Li, J. He, D. Cui, G. Lu, X. Chen, Z. Nie, Photosensitizer-loaded gold vesicles with strong plasmonic coupling effect for imaging-guided photothermal/photodynamic therapy, ACS Nano, 7 (2013) 5320-5329. [86] V.D. Badwaik, L.M. Vangala, D.S. Pender, C.B. Willis, Z.P. Aguilar, M.S. Gonzalez, R. Paripelly, R. Dakshinamurthy, Size-dependent antimicrobial properties of 52
ACCEPTED MANUSCRIPT
SC R
IP
T
sugar-encapsulated gold nanoparticles synthesized by a green method, Nanoscale Res Lett, 7 (2012) 623. [87] D. Pissuwan, C.H. Cortie, S.M. Valenzuela, M.B. Cortie, Functionalised gold nanoparticles for controlling pathogenic bacteria, Trends Biotechnol, 28 (2010) 207-213. [88] W.S. Kuo, C.N. Chang, Y.T. Chang, C.S. Yeh, Antimicrobial gold nanorods with dual-modality photodynamic inactivation and hyperthermia, Chem Commun (Camb), (2009) 4853-4855. [89] S. Wang, A.K. Singh, D. Senapati, A. Neely, H. Yu, P.C. Ray, Rapid colorimetric
MA
NU
identification and targeted photothermal lysis of salmonella bacteria by using bioconjugated oval-shaped gold nanoparticles, Chem Eur J, 16 (2010) 5600-5606. [90] G.A. Nirmala, K. Pandian, Antibacterial efficacy of aminoglycosidic antibiotics protected gold nanoparticles—A brief study, Colloid Surf A-Physicochem Eng Asp, 297 (2007) 63-70.
D
[91] G.L. Burygin, B.N. Khlebtsov, A.N. Shantrokha, L.A. Dykman, V.A. Bogatyrev, N.G. Khlebtsov, On the enhanced antibacterial activity of antibiotics mixed with gold nanoparticles, Nanoscale Res Lett, 4 (2009) 794-801. [92] M. Chamundeeswari, S.S. Sobhana, J.P. Jacob, M.G. Kumar, M.P. Devi, T.P. Sastry,
AC
CE P
TE
A.B. Mandal, Preparation, characterization and evaluation of a biopolymeric gold nanocomposite with antimicrobial activity, Biotechnol Appl Biochem, 55 (2010) 29-35. [93] V.P. Zharov, K.E. Mercer, E.N. Galitovskaya, M.S. Smeltzer, Photothermal nanotherapeutics and nanodiagnostics for selective killing of bacteria targeted with gold nanoparticles, Biophys J, 90 (2006) 619-627. [94] R.S. Norman, J.W. Stone, A. Gole, C.J. Murphy, T.L. Sabo-Attwood, Targeted photothermal lysis of the pathogenic bacteria, pseudomonas aeruginosa, with gold nanorods, Nano Lett, 8 (2008) 302-306. [95] W.C. Huang, P.-J. Tsai, Y.C. Chen, Functional gold nanoparticles as photothermal agents for selective-killing of pathogenic bacteria, Nanomedicine, 2 (2007) 777-787. [96] J. Gil-Tomas, S. Tubby, I.P. Parkin, N. Narband, L. Dekker, S.P. Nair, M. Wilson, C. Street, lethal photosensitisation of staphylococcus aureus using a toluidine blue o-tiopronin-gold nanoparticle conjugate, J Mater Chem, 17 (2007) 3739-3746. [97] H. Gu, P.L. Ho, E. Tong, L. Wang, B. Xu, Presenting vancomycin on nanoparticles to enhance antimicrobial activities, Nano Lett, 3 (2003) 1261-1263. [98] A.N. Brown, K. Smith, T.A. Samuels, J.R. Lu, S.O. Obare, M.E. Scott, Nanoparticles functionalized with ampicillin destroy multiple-antibiotic-resistant isolates of pseudomonas aeruginosa and enterobacter aerogenes and methicillin-resistant staphylococcus aureus, Appl Environ Microb, 78 (2012) 2768-2774. 53
ACCEPTED MANUSCRIPT
SC R
IP
T
[99] Y. Cui, Y. Zhao, Y. Tian, W. Zhang, X. Lu, X. Jiang, The molecular mechanism of action of bactericidal gold nanoparticles on escherichia coli, Biomaterials, 33 (2012) 2327-2333. [100] Y. Zhou, Y. Kong, S. Kundu, J.D. Cirillo, H. Liang, Antibacterial activities of gold and silver nanoparticles against escherichia coli and bacillus calmette-guerin, J Nanobiotechnology, 10 (2012) 19. [101] T.J. Berger, J.A. Spadaro, S.E. Chapin, R.O. Becker, Electrically generated silver ions: quantitative effects on bacterial and mammalian cells, Antimicrob Agents Ch, 9 (1976) 357-358.
MA
NU
[102] R. Slawson, J. Trevors, H. Lee, Silver accumulation and resistance in pseudomonas stutzeri, Arch Microbiol, 158 (1992) 398-404. [103] G. Zhao, Edward Stevens Jr, S., Multiple parameters for the comprehensive evaluation of the susceptibility of escherichia coli to the silver ion, Biometals, 11 (1998) 27-32.
D
[104] S. Silver, L.T. Phung, Bacterial heavy metal resistance: new surprises, Annu Rev Microbiol, 50 (1996) 753-789. [105] J.H. Crabtree, R.J. Burchette, R.A. Siddiqi, I.T. Huen, L.L. Hadnott, A. Fishman, The efficacy of silver-ion implanted catheters in reducing peritoneal dialysis-related
AC
CE P
TE
infections, Perit Dial Int, 23 (2003) 368-374. [106] K. Dunn, V. Edwards-Jones, The role of Acticoat with nanocrystalline silver in the management of burns, Burns, 30 Suppl 1 (2004) S1-9. [107] A. Petica, S. Gavriliu, M. Lungu, N. Buruntea, C. Panzaru, Colloidal silver solutions with antimicrobial properties, Mater Sci Eng B, 152 (2008) 22-27. [108] M. Rai, A. Yadav, A. Gade, Silver nanoparticles as a new generation of antimicrobials, Biotechnol Adv, 27 (2009) 76-83. [109] P. Jain, T. Pradeep, Potential of silver nanoparticle-coated polyurethane foam as an antibacterial water filter, Biotechnol Bioeng, 90 (2005) 59-63. [110] M. Ip, S.L. Lui, V.K. Poon, I. Lung, A. Burd, Antimicrobial activities of silver dressings: an in vitro comparison, J Med Microbiol, 55 (2006) 59-63. [111] C. Aymonier, U. Schlotterbeck, L. Antonietti, P. Zacharias, R. Thomann, J.C. Tiller, S. Mecking, Hybrids of silver nanoparticles with amphiphilic hyperbranched macromolecules exhibiting antimicrobial properties, Chem Commun (Camb), (2002) 3018-3019. [112] J. Tian, K.K.Y. Wong, C.M. Ho, C.N. Lok, W.Y. Yu, C.M. Che, P.K.H. Tam, Topical delivery of silver nanoparticles promotes wound healing, ChemMedChem, 2 (2007) 129-136. [113] P. Pallavicini, A. Taglietti, G. Dacarro, Y. Antonio Diaz-Fernandez, M. Galli, P. Grisoli, M. Patrini, G. Santucci De Magistris, R. Zanoni, Self-assembled monolayers of 54
ACCEPTED MANUSCRIPT
SC R
IP
T
silver nanoparticles firmly grafted on glass surfaces: low Ag+ release for an efficient antibacterial activity, J Colloid Interface Sci, 350 (2010) 110-116. [114] S. Chernousova, M. Epple, Silver as antibacterial agent: Ion, nanoparticle, and metal, Angew Chem Int Edit, 52 (2013) 1636-1653. [115] H.H. Lara, N.V. Ayala-Nunez, L.D.I. Turrent, C.R. Padilla, Bactericidal effect of silver nanoparticles against multidrug-resistant bacteria, World J Microb Biot, 26 (2010) 615-621. [116] S.L. Percival, P.G. Bowler, J. Dolman, Antimicrobial activity of silver-containing dressings on wound microorganisms using an in vitro biofilm model, Int Wound J, 4
MA
NU
(2007) 186-191. [117] H.H. Lara, N.V. Ayala-Nunez, L. Ixtepan-Turrent, C. Rodriguez-Padilla, Mode of antiviral action of silver nanoparticles against HIV-1, J Nanobiotechnology, 8 (2010) 1. [118] K.J. Kim, W.S. Sung, S.K. Moon, J.S. Choi, J.G. Kim, D.G. Lee, Antifungal effect of silver nanoparticles on dermatophytes, J Microbiol Biotechnol, 18 (2008) 1482-1484.
D
[119] H.L. Su, S.H. Lin, J.C. Wei, I.C. Pao, S.H. Chiao, S.Z. Lin, J.J. Lin, Novel nanohybrids of silver particles on clay platelets for inhibiting silver-resistant bacteria, PLoS One, 6 (2011) e21125. [120] J.R. Morones, J.L. Elechiguerra, A. Camacho, K. Holt, J.B. Kouri, J.T. Ramirez, M.J.
AC
CE P
TE
Yacaman, The bactericidal effect of silver nanoparticles, Nanotechnology, 16 (2005) 2346-2353. [121] I. Sondi, B. Salopek-Sondi, Silver nanoparticles as antimicrobial agent: a case study on E. coli as a model for gram-negative bacteria, J Colloid Interface Sci, 275 (2004) 177-182. [122] S. Shrivastava, T. Bera, A. Roy, G. Singh, P. Ramachandrarao, D. Dash, Characterization of enhanced antibacterial effects of novel silver nanoparticles, Nanotechnology, 18 (2007) 1-9. [123] M.L.W. Knetsch, L.H. Koole, New strategies in the development of antimicrobial coatings: The example of increasing usage of silver and silver nanoparticles, Polymers, 3 (2011) 340-366. [124] J.S. Kim, E. Kuk, K.N. Yu, J.H. Kim, S.J. Park, H.J. Lee, S.H. Kim, Y.K. Park, Y.H. Park, C.Y. Hwang, Antimicrobial effects of silver nanoparticles, Nanomed Nanotech Biol Med, 3 (2007) 95-101. [125] Q.L. Feng, J. Wu, G.Q. Chen, F.Z. Cui, T.N. Kim, J.O. Kim, A mechanistic study of the antibacterial effect of silver ions on escherichia coli and staphylococcus aureus, J Biomed Mater Res, 52 (2000) 662-668. [126] Y. Matsumura, K. Yoshikata, S.i. Kunisaki, T. Tsuchido, Mode of bactericidal action of silver zeolite and its comparison with that of silver nitrate, Appl Environ Microb, 69 (2003) 4278-4281. 55
ACCEPTED MANUSCRIPT
SC R
IP
T
[127] D.W. Hatchett, H.S. White, Electrochemistry of sulfur adlayers on the low-index faces of silver, J Phys Chem, 100 (1996) 9854-9859. [128] Y.-H. Hsin, C.-F. Chen, S. Huang, T.-S. Shih, P.-S. Lai, P.J. Chueh, The apoptotic effect of nanosilver is mediated by a ROS- and JNK-dependent mechanism involving the mitochondrial pathway in NIH3T3 cells, Toxicol Lett, 179 (2008) 130-139. [129] C. Rensing, G. Grass, Escherichia coli mechanisms of copper homeostasis in a changing environment, FEMS Microbiol Rev, 27 (2003) 197-213. [130] A.S. Gordon, L.D. Howell, V. Harwood, Responses of diverse heterotrophic bacteria to elevated copper concentrations, Can J Microbiol, 40 (1994) 408-411.
MA
NU
[131] C. Espírito Santo, P.V. Morais, G. Grass, Isolation and characterization of bacteria resistant to metallic copper surfaces, Appl Environ Microb, 76 (2010) 1341-1348. [132] K. Karlin, Metalloenzymes, structural motifs, and inorganic models, Science, 261 (1993) 701-708.
D
[133] G. Grass, C. Rensing, M. Solioz, Metallic copper as an antimicrobial surface, Appl Environ Microb, 77 (2011) 1541-1547. [134] L. Macomber, J.A. Imlay, The iron-sulfur clusters of dehydratases are primary intracellular targets of copper toxicity, Proc Natl Acad Sci U S A, 106 (2009)
AC
CE P
TE
8344-8349. [135] L.J. Wheeldon, T. Worthington, P.A. Lambert, A.C. Hilton, C.J. Lowden, T.S.J. Elliott, Antimicrobial efficacy of copper surfaces against spores and vegetative cells of clostridium difficile: the germination theory, J Antimicrob Chemother, 62 (2008) 522-525. [136] S. Mehtar, I. Wiid, S.D. Todorov, The antimicrobial activity of copper and copper alloys against nosocomial pathogens and mycobacterium tuberculosis isolated from healthcare facilities in the western cape: an in-vitro study, J hosp infect, 68 (2008) 45-51. [137] M. Ibrahim, F. Wang, M.-m. Lou, G.-l. Xie, B. Li, Z. Bo, G.-q. Zhang, H. Liu, A. Wareth, Copper as an antibacterial agent for human pathogenic multidrug resistant burkholderia cepacia complex bacteria, J Biosci Bioeng, 112 (2011) 570-576. [138] G. Faundez, M. Troncoso, P. Navarrete, G. Figueroa, Antimicrobial activity of copper surfaces against suspensions of salmonella enterica and campylobacter jejuni, BMC Microbiol, 4 (2004) 19. [139] C.E. Santo, N. Taudte, D.H. Nies, G. Grass, Contribution of copper Ion resistance to survival of Escherichia coli on metallic copper surfaces, Appl Environ Microb, 74 (2008) 977-986. [140] W.-X. Tian, S. Yu, M. Ibrahim, A. Almonaofy, L. He, Q. Hui, Z. Bo, B. Li, G.-l. Xie, Copper as an antimicrobial agent against opportunistic pathogenic and multidrug 56
ACCEPTED MANUSCRIPT
SC R
IP
T
resistant Enterobacter bacteria, J Microbiol, 50 (2012) 586-593. [141] J.O. Noyce, H. Michels, C.W. Keevil, Potential use of copper surfaces to reduce survival of epidemic meticillin-resistant staphylococcus aureus in the healthcare environment, J hosp infect, 63 (2006) 289-297. [142] G. Steindl, , S. Heuberger, B. Springer, Antimicrobial effect of copper on multidrug-resistant bacteria, Wien Tierarztl Monat, 99 (2012) 38-43. [143] C.E. Santo, E.W. Lam, C.G. Elowsky, D. Quaranta, D.W. Domaille, C.J. Chang, G. Grass, Bacterial killing by dry metallic copper surfaces, Appl Environ Microb, 77 (2011) 794-802.
MA
NU
[144] S.L. Warnes, S.M. Green, H.T. Michels, C.W. Keevil, Biocidal efficacy of copper alloys against pathogenic enterococci Involves degradation of genomic and plasmid DNAs, Appl Environ Microb, 76 (2010) 5390-5401. [145] W.-X. Tian, S. Yu, M. Ibrahim, A.W. Almonaofy, L. He, Q. Hui, Z. Bo, B. Li, G.-l. Xie, Copper as an antimicrobial agent against opportunistic pathogenic and multidrug
D
resistant enterobacter bacteria, Journal of Microbiology, 50 (2012) 586-593. [146] N. Cioffi, L. Torsi, N. Ditaranto, G. Tantillo, L. Ghibelli, L. Sabbatini, T. Bleve-Zacheo, M. D'Alessio, P.G. Zambonin, E. Traversa, Copper nanoparticle/polymer composites with antifungal and bacteriostatic properties, Chem Mater, 17 (2005)
AC
CE P
TE
5255-5262. [147] M. Gouda, A. Hebeish, Preparation and evaluation of CuO/Chitosan nanocomposite for antibacterial finishing cotton fabric, J Ind Text, 39 (2010) 203-214. [148] N.C. Cady, J.L. Behnke, A.D. Strickland, Copper-based nanostructured coatings on natural Cellulose: Nanocomposites exhibiting rapid and efficient inhibition of a multi-drug resistant wound pathogen, A. baumannii, and mammalian cell biocompatibility in vitro, Adv Eng Mater, 21 (2011) 2506-2514. [149] C. Gunawan, W.Y. Teoh, C.P. Marquis, R. Amal, Cytotoxic origin of copper(II) oxide nanoparticles: Comparative studies with micron-sized particles, leachate, and metal salts, ACS Nano, 5 (2011) 7214-7225. [150] P. Maniprasad, S. Santra, Novel copper (Cu) loaded core-shell silica nanoparticles with improved cu bioavailability: synthesis, characterization and study of antibacterial properties, J Biomed Nanotechnol, 8 (2012) 558-566. [151] R.R.V.a.J.B. A, Nanoparticles and their potential application as antimicrobials, science against microbial pathogens: communicating current research and technological advances, 1 (2011) 13. [152] J.T. Seil, T.J. Webster, Antibacterial effect of zinc oxide nanoparticles combined with ultrasound, Nanotechnology, 23 (2012) 495101. [153] A. Pramanik, D. Laha, D. Bhattacharya, P. Pramanik, P. Karmakar, A novel study of antibacterial activity of copper iodide nanoparticle mediated by DNA and 57
ACCEPTED MANUSCRIPT
SC R
IP
T
membrane damage, Colloids Surf B Biointerfaces, 96 (2012) 50-55. [154] C. Renz, Lichtreaktionen der Oxyde des Titans, Cers und der Erdsäuren, Helvetica Chimica Acta, 4 (1921) 961-968. [155] M.N. Chong, B. Jin, C.W.K. Chow, C. Saint, Recent developments in photocatalytic water treatment technology: A review, Water Res, 44 (2010) 2997-3027. [156] N.G. Chorianopoulos, D.S. Tsoukleris, E.Z. Panagou, P. Falaras, G.J.E. Nychas, Use of titanium dioxide (TiO2) photocatalysts as alternative means for Listeria monocytogenes biofilm disinfection in food processing, Food Microbiol, 28 (2011)
MA
NU
164-170. [157] D. Li, H. Haneda, S. Hishita, N. Ohashi, Visible-light-driven N−F−Codoped TiO2 ppotocatalysts. 2. optical characterization, photocatalysis, and potential application to air purification, Chem Mater, 17 (2005) 2596-2602. [158] L. Cermenati, P. Pichat, C. Guillard, A. Albini, Probing the TiO2 photocatalytic
D
mechanisms in water purification by use of quinoline, photo-fenton generated OH• radicals and superoxide Dismutase†, J Phys Chem B, 101 (1997) 2650-2658. [159] G. Fu, P.S. Vary, C.T. Lin, Anatase TiO2 nanocomposites for antimicrobial coatings, J Phys Chem B, 109 (2005) 8889-8898.
AC
CE P
TE
[160] Q. Li, S. Mahendra, D.Y. Lyon, L. Brunet, M.V. Liga, D. Li, P.J.J. Alvarez, Antimicrobial nanomaterials for water disinfection and microbial control: Potential applications and implications, Water Res, 42 (2008) 4591-4602. [161] R. Dastjerdi, M. Montazer, A review on the application of inorganic nano-structured materials in the modification of textiles: Focus on anti-microbial properties, Colloids Surf B Biointerfaces, 79 (2010) 5-18. [162] T. Miyagi, M. Kamei, T. Mitsuhashi, T. Ishigaki, A. Yamazaki, Charge separation at the rutile/anatase interface: a dominant factor of photocatalytic activity, Chemical Physics Lett, 390 (2004) 399-402. [163] R.R. Shah, S. Kaewgun, B.I. Lee, T.-R.J. Tzeng, The antibacterial effects of biphasic brookite-anatase titanium dioxide nanoparticles on multiple-drug-resistant Staphylococcus aureus, J Biomed Nanotechnol, 4 (2008) 339-348. [164] W.A. Daoud, J.H. Xin, Y.-H. Zhang, Surface functionalization of cellulose fibers with titanium dioxide nanoparticles and their combined bactericidal activities, Surf Sci, 599 (2005) 69-75. [165] P. Hajkova, P. Spatenka, J. Horsky, I. Horska, A. Kolouch, Photocatalytic effect of TiO2 films on viruses and bacteria, Plasma Process Polym, 4 (2007) S397-S401. [166] N.M. Mahmoodi, M. Arami, N.Y. Limaee, N.S. Tabrizi, Kinetics of heterogeneous photocatalytic degradation of reactive dyes in an immobilized TiO2 photocatalytic reactor, J Colloid Interface Sci, 295 (2006) 159-164. 58
ACCEPTED MANUSCRIPT
SC R
IP
T
[167] D.W. Sheel, L.A. Brook, I.B. Ditta, P. Evans, H.A. Foster, A. Steele, H.M. Yates, biocidal silver and silver/titania composite films grown by chemical vapour deposition, Int J Photoenergy 2008 (2008). [168] A. Erkan, U. Bakir, G. Karakas, Photocatalytic microbial inactivation over Pd doped SnO2 and TiO2 thin films, J Photoch Photobio A, 184 (2006) 313-321. [169] A. Pal, S.O. Pehkonen, L.E. Yu, M.B. Ray, Photocatalytic inactivation of gram-positive and gram-negative bacteria using fluorescent light, J Photoch Photobio A, 186 (2007) 335-341. [170] T. Matsunaga, R. Tomoda, T. Nakajima, N. Nakamura, T. Komine,
MA
NU
Continuous-sterilization system that uses photosemiconductor powders, Appl Environ Microb, 54 (1988) 1330-1333. [171] T. Saito, T. Iwase, J. Horie, T. Morioka, Mode of photocatalytic bactericidal action of powdered semiconductor TiO2 on mutans streptococci, J Photoch Photobio B, 14 (1992) 369-379.
D
[172] P. Amézaga-Madrid, R. Silveyra-Morales, L. Córdoba-Fierro, G.V. Nevárez-Moorillón, M. Miki-Yoshida, E. Orrantia-Borunda, Solı, amp, x, F.J. s, TEM evidence of ultrastructural alteration on pseudomonas aeruginosa by photocatalytic TiO2 thin films, J Photoch Photobio B, 70 (2003) 45-50.
AC
CE P
TE
[173] P. Amézaga-Madrid, G.V. Nevárez-Moorillón, E. Orrantia-Borunda, M. Miki-Yoshida, Photoinduced bactericidal activity against pseudomonas aeruginosa by TiO2 based thin films, FEMS Microbiol Rev, 211 (2002) 183-188. [174] C. Hu, J. Guo, J. Qu, X. Hu, Photocatalytic degradation of pathogenic bacteria with AgI/TiO2 under visible light irradiation, Langmuir, 23 (2007) 4982-4987. [175] J.W. Liou, H.H. Chang, Bactericidal Effects and Mechanisms of visible light-responsive titanium dioxide photocatalysts on pathogenic bacteria, Arch Immunol Ther Exp, 60 (2012) 267-275. [176] C. Wei, W.Y. Lin, Z. Zainal, N.E. Williams, K. Zhu, A.P. Kruzic, R.L. Smith, K. Rajeshwar, Bactericidal activity of TiO2 photocatalyst in aqueous media: Toward a solar-assisted water disinfection system, Environ Toxicol Chem, 28 (1994) 934-938. [177] R.R.K. Shah, Sujaree; Lee, Burtrand I.; Tzeng, Tzuen-Rong J., The antibacterial fffects of biphasic brookite-Anatase titanium dioxide nanoparticles on multiple-drug-Resistant staphylococcus aureus, J Biomed Nanotechnol, 4 (2008) 339-348. [178] S. Ciston, R.M. Lueptow, K.A. Gray, Controlling biofilm growth using reactive ceramic ultrafiltration membranes, J Membr Sci, 342 (2009) 263-268. [179] P. Dhandapani, S. Maruthamuthu, G. Rajagopal, Bio-mediated synthesis of TiO2 nanoparticles and its photocatalytic effect on aquatic biofilm, J Photoch Photobio B, 110 (2012) 43-49. 59
ACCEPTED MANUSCRIPT
SC R
IP
T
*180+ .l. Simon-Deckers, S. oo, M. Mayne- hermite, N. Herlin-Boime, N. Menguy, C.c. eynaud, B. ouget, M. Carri re, Size-, composition- and shape-dependent toxicological impact of metal oxide nanoparticles and carbon nanotubes toward bacteria, Environ Toxicol Chem, 43 (2009) 8423-8429. [181] T. Szabó, J. Németh, I. Dékány, Zinc oxide nanoparticles incorporated in ultrathin layer silicate films and their photocatalytic properties, Colloids Surf A Physicochem Eng Asp, 230 (2003) 23-35. [182] O. Yamamoto, J. Sawai, T. Sasamoto, Change in antibacterial characteristics with doping amount of ZnO in MgO–ZnO solid solution, Int J Inorg Mater 2(2000)
MA
NU
451-454. [183] M. Ansari, H. Khan, A. Khan, A. Sultan, A. Azam, Synthesis and characterization of the antibacterial potential of ZnO nanoparticles against extended-spectrum β-lactamases-producing escherichia coli and klebsiella pneumoniae isolated from a tertiary care hospital of North India, Appl Microbiol Biotechnol, 94 (2012) 467-477.
D
[184] R. Brayner, R. Ferrari-Iliou, N. Brivois, S. Djediat, M.F. Benedetti, F. Fiévet, Toxicological impact studies based on Escherichia coli bacteria in ultrafine ZnO nanoparticles colloidal medium, Nano Lett, 6 (2006) 866-870. [185] D. Sharma, J. Rajput, B.S. Kaith, M. Kaur, S. Sharma, Synthesis of ZnO
AC
CE P
TE
nanoparticles and study of their antibacterial and antifungal properties, Thin Solid Films, 519 (2010) 1224-1229. [186] S. Ikawa, K. Kitano, S. Hamaguchi, Effects of pH on bactberial inactivation in aqueous solutions due to low-temperature atmospheric pressure plasma application, Plasma Process Polym, 7 (2010) 33-42. [187] N. Jones, B. Ray, K.T. Ranjit, A.C. Manna, Antibacterial activity of ZnO nanoparticle suspensions on a broad spectrum of microorganisms, FEMS Microbiol Rev, 279 (2008) 71-76. [188] J. Sawai, T. Yoshikawa, Quantitative evaluation of antifungal activity of metallic oxide powders (MgO, CaO and ZnO) by an indirect conductimetric assay, J Appl Microbiol, 96 (2004) 803-809. [189] N. Padmavathy, R. Vijayaraghavan, Enhanced bioactivity of ZnO nanoparticles—an antimicrobial study, Sci Technol Adv Mat 9(2008) 1-7. [190] O.B. Koper, I. Lagadic, A. Volodin, K.J. Klabunde, Alkaline-Earth oxide nanoparticles obtained by aerogel methods. Characterization and rational for unexpectedly high surface chemical reactivities, Chem Mater, 9 (1997) 2468-2480. [191] O.B. Koper, J.S. Klabunde, G.L. Marchin, K.J. Klabunde, P. Stoimenov, L. Bohra, Nanoscale powders and formulations with biocidal activity toward spores and vegetative cells of bacillus species, viruses, and toxins, Curr Microbiol, 44 (2002) 49-55. 60
ACCEPTED MANUSCRIPT
SC R
IP
T
[192] J. Sawai, H. Kojima, H. Igarashi, A. Hashimoto, S. Shoji, T. Sawaki, A. Hakoda, E. Kawada, T. Kokugan, M. Shimizu, Antibacterial characteristics of magnesium oxide powder, World J Microb Biot, 16 (2000) 187-194. [193] K. Blecher, A. Nasir, A. Friedman, The growing role of nanotechnology in combating infectious disease, Virulence, 2 (2011) 395-401. [194] N. Awaya, T. Kobayashi, Self-Aligned passivation technology for copper interconnection using Copper-Aluminum alloy, Jpn J Appl Phys, 36 (1997) 112-114 [195] B.K. Li, B.E. Logan, Bacterial adhesion to glass and metal-oxide surfaces, Colloid Surface B, 36 (2004) 81-90.
MA
NU
[196] A. Mukherjee, I, Mohammed Sadiq, T.C. Prathna, N. Chandrasekaran, microbial activity of aluminium oxide nanoparticles for potential clinical applications, Science against microbial pathogens, Science against microbial pathogens: communicating current research and technological advances, (2011) 245-251. [197] V.K. Mishra, H. P. Pandey, G. Mohammad, Antioxidant properties of some
D
nanoparticle may enhance wound healing in T2DM patients., Dig J Nanomater Bios 3(2008) 159-162. [198] I.M. Sadiq, T.C. Prathna, N. Chandrasekaran, A. Mukherjee, Antimicrobial activity of aluminium oxide nanoparticles for potential clinical applications, Science
AC
CE P
TE
against microbial pathogens: communicating current research and technological advances 1(2011) 245-251. [199] I.M. Sadiq, B. Chowdhury, N. Chandrasekaran, A. Mukherjee, Antimicrobial sensitivity of Escherichia coli to alumina nanoparticles, Nanomed Nanotechnol Biol Med, 5 (2009) 282-286. [200] Z. Qiu, Y. Yu, Z. Chen, M. Jin, D. Yang, Z. Zhao, J. Wang, Z. Shen, X. Wang, D. Qian, A. Huang, B. Zhang, J.W. Li, Nanoalumina promotes the horizontal transfer of multiresistance genes mediated by plasmids across genera, Proc Natl Acad Sci U S A, 109 (2012) 4944-4949. [201] H. Xu, F. Qu, H. Xu, W. Lai, Y. Andrew Wang, Z. Aguilar, H. Wei, Role of reactive oxygen species in the antibacterial mechanism of silver nanoparticles on escherichia coli O157:H7, Biometals, 25 (2012) 45-53. [202] I. Chopra, The increasing use of silver-based products as antimicrobial agents: a useful development or a cause for concern?, J Antimicrob Chemother, 59 (2007) 587-590. [203] G. Subbiahdoss, S. Sharifi, D.W. Grijpma, S. Laurent, H.C. van der Mei, M. Mahmoudi, H.J. Busscher, Magnetic targeting of surface-modified superparamagnetic iron oxide nanoparticles yields antibacterial efficacy against biofilms of gentamicin-resistant staphylococci, Acta Biomaterialia, 8 (2012) 2047-2055. [204] R. Gokulakrishnan, S. Ravikumar, J.A. Raj, In vitro antibacterial potential of 61
ACCEPTED MANUSCRIPT
SC R
IP
T
metal oxide nanoparticles against antibiotic resistant bacterial pathogens, Asian Pacific Journal of Tropical Disease, 2 (2012) 411-413. [205] R. Hernandez-Delgadillo, D. Velasco-Arias, D. Diaz, K. Arevalo-Nino, M. Garza-Enriquez, M.A. De la Garza-Ramos, C. Cabral-Romero, Zerovalent bismuth nanoparticles inhibit streptococcus mutans growth and formation of biofilm, Int J Nanomedicine, 7 (2012) 2109-2113. [206] M.A. Syed, U. Manzoor, I. Shah, S.H. Bukhari, Antibacterial effects of tungsten nanoparticles on the escherichia coli strains isolated from catheterized urinary tract infection (UTI) cases and staphylococcus aureus, New Microbiol, 33 (2010) 329-335.
MA
NU
[207] A. Roy, S.S. Gauri, M. Bhattacharya, J. Bhattacharya, Antimicrobial activity of caO nanoparticles, J Biomed Nanotechnol, 9 (2013) 1570-1578. [208] B. Wu, R. Huang, M. Sahu, X. Feng, P. Biswas, Y.J. Tang, Bacterial responses to Cu-doped TiO2 nanoparticles, Science of The Total Environment, 408 (2010) 1755-1758.
D
[209] E. Fröhlich, E. Roblegg, Models for oral uptake of nanoparticles in consumer products, Toxicology, 291 (2012) 10-17. [210] T.J. Brunner, P. Wick, P. Manser, P. Spohn, R.N. Grass, L.K. Limbach, A. Bruinink, W.J. Stark, In vitro cytotoxicity of oxide nanoparticles: Comparison to asbestos,
AC
CE P
TE
silica, and the effect of particle solubility, Environ Toxicol Chem, 40 (2006) 4374-4381. [211] R.F. Hamilton, N. Wu, D. Porter, M. Buford, M. Wolfarth, A. Holian, Particle length-dependent titanium dioxide nanomaterials toxicity and bioactivity, Part Fibre Toxicol, 6 (2009) 35. [212] Y.S. Chen, Y.C. Hung, I. Liau, G.S. Huang, Assessment of the in vivo toxicity of gold nanoparticles, Nanoscale Res Lett, 4 (2009) 858-864. [213] H.S. Choi, W. Liu, P. Misra, E. Tanaka, J.P. Zimmer, B. Itty Ipe, M.G. Bawendi, J.V. Frangioni, Renal clearance of quantum dots, Nat Biotechnol, 25 (2007) 1165-1170. [214] F. Schrurs, D. Lison, Focusing the research efforts, Nat Nanotechnol, 7 (2012) 546-548. [215] Join the dialogue, Nat Nanotechnol, 7 (2012) 545. [216] M.D. Adhikari, S. Goswami, B.R. Panda, A. Chattopadhyay, A. Ramesh, Membrane-directed high bactericidal activity of (gold nanoparticle)-polythiophene composite for niche applications against pathogenic bacteria., Adv Healthcare Mater, 2 (4) (2013). [217] S. Shrivastava, T. Bera, A. Roy, G. Singh, P. Ramachandrarao, D. Dash, Characterization of enhanced antibacterial effects of novel silver nanoparticles, Nanotechnology, 18 (2007) 225103. *218+ . Panáček, . Kvítek, . Prucek, M. Kolář, . Večeřová, N. Pizúrová, V.K. Sharma, T.j. Nevěčná, . Zbořil, Silver colloid nanoparticles: synthesis, characterization, and 62
ACCEPTED MANUSCRIPT
SC R
IP
T
their antibacterial activity, J Phys Chem B, 110 (2006) 16248-16253. [219] D. Jain, S. Kachhwaha, R. Jain, G. Srivastava, S.L. Kothari, Novel microbial route to synthesize silver nanoparticles using spore crystal mixture of Bacillus thuringiensis, Indian J Exp Biol, 48 (2010) 1152-1156. [220] A. Nanda, M. Saravanan, Biosynthesis of silver nanoparticles from staphylococcus aureus and its antimicrobial activity against MRSA and MRSE, Nanomed Nanotechnology Biol Med, 5 (2009) 452-456. [221] M. Saravanan, A. Nanda, Extracellular synthesis of silver bionanoparticles from aspergillus clavatus and its antimicrobial activity against MRSA and MRSE, Colloids
MA
NU
Surf B Biointerfaces, 77 (2010) 214-218. [222] S.V. Otari, R.M. Patil, S.R. Waghmare, S.J. Ghosh, S.H. Pawar, A novel microbial synthesis of catalytically active Ag-alginate biohydrogel and its antimicrobial activity, Dalton Trans, 42 (2013) 9966-9975. [223] M. Doudi, N. Naghsh, M. Setorki, Comparison of the effects of silver
D
nanoparticles on pathogenic bacteria resistant to beta-lactam antibiotics (ESBLs) as a prokaryote model and wistar rats as a eukaryote model, Med Sci Monit Basic Res, 19 (2013) 103-110. [224] M. Ansari, H. Khan, A. Khan, A. Malik, A. Sultan, M. Shahid, F. Shujatullah, A.
AC
CE P
TE
Azam, Evaluation of antibacterial activity of silver nanoparticles against MSSA and MRSA on isolates from skin infections, Biol Med 3(2011) 141-146. [225] H. Lara, N. Ayala-Núñez, L. Ixtepan Turrent, C. Rodríguez Padilla, Bactericidal effect of silver nanoparticles against multidrug-resistant bacteria, World J Microbiol Biotechnol, 26 (2010) 615-621. [226] M. Eid, E. Araby, Bactericidal effect of poly(acrylamide/itaconic acid)–silver nanoparticles synthesized by gamma irradiation gainst Pseudomonas Aeruginosa, Appl Biochem Biotechnol, 171 (2013) 469-487. [227] P. Jena, S. Mohanty, R. Mallick, B. Jacob, A. Sonawane, Toxicity and antibacterial assessment of chitosan-coated silver nanoparticles on human pathogens and macrophage cells, Int J Nanomedicine, 7 (2012) 1805-1818. [228] V. Sambhy, M.M. MacBride, B.R. Peterson, A. Sen, Silver bromide nanoparticle/polymer composites: dual action tunable antimicrobial materials, J Am Chem Soc, 128 (2006) 9798-9808. [229] G. Ren, D. Hu, E.W.C. Cheng, M.A. Vargas-Reus, P. Reip, R.P. Allaker, Characterisation of copper oxide nanoparticles for antimicrobial applications, Int J Antimicrob Agents, 33 (2009) 587-590. [230] J. Lellouche, E. Kahana, S. Elias, A. Gedanken, E. Banin, Antibiofilm activity of nanosized magnesium fluoride, Biomaterials, 30 (2009) 5969-5978. [231] E.N. Taylor, K.M. Kummer, N.G. Durmus, K. Leuba, K.M. Tarquinio, T.J. Webster, 63
ACCEPTED MANUSCRIPT
SC R
IP
T
Superparamagnetic iron oxide nanoparticles (SPION) for the treatment of antibiotic-resistant biofilms, Small, 8 (2012) 3016-3027. [232] M. Mahmoudi, V. Serpooshan, Silver-Coated Engineered magnetic nanoparticles are promising for the success in the fight against antibacterial resistance Threat, ACS Nano, 6 (2012) 2656-2664. [233] R.K. Kunkalekar, M.M. Naik, S.K. Dubey, A.V. Salker, Antibacterial activity of silver-doped manganese dioxide nanoparticles on multidrug-resistant bacteria, J Chem Technol Biotechnol, 88 (2013) 873-877. [234] J.F. Hillyer, R.M. Albrecht, Gastrointestinal persorption and tissue distribution of
MA
NU
differently sized colloidal gold nanoparticles, J Pharm Sci, 90 (2001) 1927-1936. [235] X.D. Zhang, H.Y. Wu, D. Wu, Y.Y. Wang, J.H. Chang, Z.B. Zhai, A.M. Meng, P.X. Liu, L.A. Zhang, F.Y. Fan, Toxicologic effects of gold nanoparticles in vivo by different administration routes, Int J Nanomedicine, 5 (2010) 771-781. [236] X.D. Zhang, D. Wu, X. Shen, P.X. Liu, N. Yang, B. Zhao, H. Zhang, Y.M. Sun, L.A.
D
Zhang, F.Y. Fan, Size-dependent in vivo toxicity of PEG-coated gold nanoparticles, Int J Nanomed, 6 (2011) 2071-2081. [237] S. Dhar, V. Mali, S. Bodhankar, A. Shiras, B.L.V. Prasad, V. Pokharkar, Biocompatible gellan gum-reduced gold nanoparticles: cellular uptake and subacute
AC
CE P
TE
oral toxicity studies, J Appl Toxicol 31 (2011) 411-420. [238] Y.S. Kim, Kim, J.S., Cho, H.S., Rha, D.S., Kim, J.M., Park, J.D., Choi, B.S., Lim, R., Chang, H.K., Chung, Y.H., Kwon, I.H., Jeong, J., Han, B.S., Yu, I.J., Twenty-Eight-Day oral toxicity, genotoxicity, and gender-related tissue distribution of silver nanoparticles in sprague-dawley rats, Inhal Toxicol 20 (2008) 575-583. [239] E.J. Park, E. Bae, J. Yi, Y. Kim, K. Choi, S. H. Lee, J. Yoon, B. C. Lee, K. Park, Repeated-dose toxicity and inflammatory responses in mice by oral administration of silver nanoparticles, Environ Toxicol Pharmacol, 30 (2010) 162-168. [240] Z. Chen, H. Meng, G. Xing, C. Chen, Y. Zhao, G. Jia, T. Wang, H. Yuan, C. Ye, F. Zhao, Z. Chai, C. Zhu, X. Fang, B. Ma, L. Wan, Acute toxicological effects of copper nanoparticles in vivo, Toxicol Lett 163 (2006) 109-120. [241] R. Lei, C. Wu, B. Yang, H. Ma, C. Shi, Q. Wang, Q. Wang, Y. Yuan, M. Liao, Integrated metabolomic analysis of the nano-sized copper particle-induced hepatotoxicity and nephrotoxicity in rats: a rapid in vivo screening method for nanotoxicity, Toxicol Appl Pharmacol, 232 (2008) 292-301. [242] Y. Duan, N. Li, C. Liu, H. Liu, Y. Cui, H. Wang, F. Hong, Interaction between nanoparticulate anatase TiO2 and lactate dehydrogenase, Biol Trace Elem Res, 136 (2010) 302-313. [243] N. Li, Y. Duan, M. Hong, L. Zheng, M. Fei, X. Zhao, J. Wang, Y. Cui, H. Liu, J. Cai, S. Gong, H. Wang, F. Hong, Spleen injury and apoptotic pathway in mice caused by 64
ACCEPTED MANUSCRIPT
SC R
IP
T
titanium dioxide nanoparticules, Toxicol Lett, 195 (2010) 161-168. [244] Q. Bu, G. Yan, P. Deng, F. Peng, H. Lin, Y. Xu, Z. Cao, T. Zhou, A. Xue, Y. Wang, X. Cen, Y.L. Zhao, NMR-based metabonomic study of the sub-acute toxicity of titanium dioxide nanoparticles in rats after oral administration, Nanotechnology, 21 (2010) 125105. [245] J. Chen, X. Dong, J. Zhao, G. Tang, In vivo acute toxicity of titanium dioxide nanoparticles to mice after intraperitioneal injection, J Appl Toxicol, 29 (2009) 330-337. [246] B. Wang, W. Feng, M. Wang, T. Wang, Y. Gu, M. Zhu, H. Ouyang, J. Shi, F. Zhang,
MA
NU
Y. Zhao, Z. Chai, H. Wang, J. Wang, Acute toxicological impact of nano- and submicro-scaled zinc oxide powder on healthy adult mice, J Nanopart Res, 10 (2008) 263-276. [247] C.M. Sayes, K.L. Reed, D.B. Warheit, Assessing toxicity of fine and nanoparticles: comparing in vitro measurements to in vivo pulmonary toxicity
AC
CE P
TE
D
profiles, Toxicol Sci, 97 (2007) 163-180.
65
AC
CE P
TE
D
MA
NU
SC R
IP
T
ACCEPTED MANUSCRIPT
Graphical abstract
66