Microbial communication: A significant approach for new leads

SAJB-01865; No of Pages 10 South African Journal of Botany xxx (2017) xxx–xxx

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South African Journal of Botany journal homepage: www.elsevier.com/locate/sajb

Review

Microbial communication: A significant approach for new leads M.A. Abdalla a,b,⁎, S. Sulieman c, L.J. McGaw a,⁎⁎ a b c

Phytomedicine Programme, Department of Paraclinical Sciences, Faculty of Veterinary Science, University of Pretoria, Private Bag X04, Onderstepoort 0110, South Africa Department of Food Science and Technology, Faculty of Agriculture, University of Khartoum, 13314 Khartoum North, Sudan Department of Agronomy, Faculty of Agriculture, University of Khartoum, 13314 Khartoum North, Sudan

a r t i c l e

i n f o

Article history: Received 21 June 2017 Received in revised form 28 September 2017 Accepted 3 October 2017 Available online xxxx Edited by A Romano Keywords: Co-culture Secondary metabolism Cryptic pathways Microbial interactions

a b s t r a c t A significant number of naturally occurring secondary metabolites from plants and microbes have been explored for their pharmacological properties and used as drugs, for example to combat infectious diseases, in human and animal health. Unfortunately, antibiotic resistance is growing faster than the discovery of new antibiotics. With this in mind, a more targeted search for lead compounds by investigating new sources and applying alternative approaches and strategies is necessary. Many recent studies confirm that most secondary metabolite gene clusters in microorganisms, especially in fungi, are silent under laboratory growth conditions. These findings lead to a better understanding of the basic principles of the chemical communication between different microorganisms in nature as they form close communities, such as interactions between fungi − bacteria, fungi − fungi, bacteria − bacteria and microorganisms existing as endophytes within their host plants. The influences of these associations in nature establish, restore and sustain the great biosynthetic potential of secondary metabolite formation. Mixed fermentation or co-cultivation represents an important approach of inducing secondary metabolism by providing appropriate physiological conditions, including competition and communication between microorganisms. This report reviews several relevant co-culturing experiments and their influences on natural product biosynthesis and methods recently used to identify the compounds afforded by co-cultivation. The medicinal importance of microbial co-cultures is also discussed. © 2017 SAAB. Published by Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Influences of microbial co-cultures on production of secondary metabolites . . . . . . . . . . . . 2.1. Bacterial-fungal co-culture as a dynamic way to induce silent gene clusters . . . . . . . . . 2.2. Bacterial-bacterial co-cultures and their potential to induce secondary metabolite biosynthesis 2.3. Fungal-fungal co-cultures and their role in producing secondary metabolites . . . . . . . . 3. Biological importance of microbial co-culture . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Analytical methods used to identify natural products induced by co-culture . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction In recent years, a wide range of biologically active secondary metabolites produced by bacteria and fungi have attracted considerable interest ⁎ Corresponding author at: Phytomedicine Programme, Department of Paraclinical Sciences, Faculty of Veterinary Science, University of Pretoria, Private Bag X04, Onderstepoort 0110, South Africa. ⁎⁎ Corresponding author. E-mail addresses: [email protected] (M.A. Abdalla), [email protected] (L.J. McGaw).

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(Abdalla et al., 2010; Jumpathong et al., 2010; Abdalla et al., 2011a, 2011b; Zinad et al., 2011; Abdalla and Matasyoh, 2014). Microorganisms co-exist in close associations, where they interact and communicate with each other (Strobel and Daisy, 2003; Aly et al., 2011). The chemical communication between different microbes in their respective habitats is based mainly on the presence of natural products, which act as signaling molecules involved in interaction, competition and different defense mechanisms (Ola et al., 2013). Two types of microbial competition can occur in the ecological system: interference and scramble competition. These can take place either within or between species.

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Interference competition takes place when one type of microorganism keeps nutrients away from another. Scramble competition takes place when one type of microorganism consumes nutrients before another. Of course, competition becomes more intense when nutrients are scarce. Microbial co-culture holds much potential for the discovery of sustained production of secondary metabolites, which can be achieved under laboratory conditions. Mixed fermentation or microbial coculture together with microbial transformation, genome mining and unculturable microorganisms have been recently discovered to be important reservoirs of novel antibiotics (Wilson et al., 2014; Ling et al., 2015). The role of secondary metabolites is important in acting as defense molecules against different predators of the producers, and inhibiting the growth of competitors (Davies, 1990). Several recent studies have discussed numerous co-culturing combinations such as fungal-bacterial, fungal-fungal and bacterial-bacterial interactions and their positive impact on new compound formation. Successful co-cultivation experiments can be mediated through signaling molecules or intimate contact, where the fungal mycelia and bacterial filaments of both microorganisms connect together as shown in Fig. 1. An excellent example of the intimate physical interaction of fungus and bacterium has been observed in a co-culture of Aspergillus nidulans and Streptomyces hygroscopicus (Schroeckh et al., 2009). This study discovered that silent gene clusters of secondary metabolism of A. nidulans are only stimulated when the fungus is co-cultivated with a bacterium and the microorganisms could physically interact. These findings support the view that not only diffusible molecules can induce cryptic biosynthetic genes in microbial communication, but that close physical interaction can have the same effect. Fungal-fungal co-cultures and their promising effects on inducing natural products have been extensively discussed (Li et al., 2011; Zhu et al., 2013). Moreover, fungal-fungal interactions are potentially significant when mycelia of different species meet and closely interact in the area of physical contact, known as the interaction zone. These responses enhance modifications in the morphology of the mycelium, as well as production of extra-cellular enzymes and natural products (Griffith et al., 1994; Rayner et al., 1994; Boddy, 2000; Woodward and Boddy, 2008). It is important to note that sub-elements, such as protein domains, from bacterial and fungal systems have potential use in many applications, such as using sequences of the protein domain of a fungal non-ribosomal peptide synthetase (NRPS) to convert a similar gene in Bacillus subtilis. This application induced the production of novel secondary metabolites (Frey-Klett et al., 2011). In general, through possible gene activation, a number of different combinations of mixed fermentation have proven their capabilities to enhance natural product biosynthesis. Herein, we report various previously investigated microbial co-culturing experiments and highlight the medicinal significance of

Fig. 1. Intimate physical contact between fungus and bacterium induces the cryptic biosynthetic pathway of secondary metabolism.

microbial mixed fermentation as a powerful tool for discovering new bioactive secondary metabolites. 2. Influences of microbial co-cultures on production of secondary metabolites 2.1. Bacterial-fungal co-culture as a dynamic way to induce silent gene clusters Several studies of bacterial-fungal interactions have confirmed coculturing as a potential tool for inducing secondary metabolites (Abdalla and Sulieman, 2017). In the early 2000s, Fenical et al. discovered a chlorinated benzophenone named pestalone (1), which is produced when the marine fungus Pestalotia is co-cultivated with a unicellular marine bacterium, strain CNJ-328 (Cueto et al., 2001). Compound 1 showed antibacterial activity against methicillin-resistant Staphylococcus aureus and against vancomycin-resistant Enterococcus faecium, in addition to in vitro cytotoxicity in the National Cancer Institute's 60 Human Tumor Cell Line Screen. Co-culturing the marine bacterium α-proteobacterium (Strain CNJ-328) with the marine-derived fungus Libertella sp. induced the synthesis of the novel diterpenoids, libertellenones A–D (2–5) (Oh et al., 2005). Terpenoids are generally known as fungal and plant metabolites and are rarely produced by bacteria (Turner and Aldridge, 1983; Hefter et al., 1993), and there is strong evidence that these diterpenoids were produced by the fungus. It can be assumed that the fungal biosynthetic gene cluster of compounds 2–5 was activated in the presence of the bacterium in the same culture. Several co-cultures of Aspergillus fumigatus and various Streptomyces spp., such as S. peucetius, induced the biosynthesis of formyl xanthocillin analogues (Zuck et al., 2011). Fumiformamide (6) and N,N′-(1Z,3Z)-1,4bis(4-methoxyphenyl)buta-1,3-diene-2,3-diyl)diformamide (7) are new compounds produced by this co-culture (Table 1). A. fumigatus was co-cultivated with the soil-derived S. bullii, isolated from the Atacama Desert, in South America, producing 10 compounds, including seven diketopiperazine alkaloids in addition to pseurotins 11-Omethylpseurotin A and its new isomer, 11-O-methylpseurotin A2 (8) (Rateb et al., 2013). Mixed fermentation of A. fumigatus and Streptomyces rapamycinicus yielded the new fungal-derived polyketides fumicyclines A (9) and B (10) (König et al., 2013), confirming that close intimacy of the fungus and bacterium is very important in inducing the fungal metabolites. The study concluded that the presence of S. rapamycinicus modifies the gene expression in A. fumigatus by modulating its regulatory processes. Another study demonstrated that physical interaction between A. nidulans and S. hygroscopicus ATCC 29253 activated the expression of the fungal genes that were responsible for the synthesis of the polyketide metabolites known as orsellinic acid (11), lecanoric acid (12), F-9775A (13), and F-9775B (14) (Schroeckh et al., 2009). Interestingly, compounds 13 and 14, which were partially derived from orsellinic acid (11), had previously been isolated from Paecilomyces carneus (Satou et al., 1999) and were not known as metabolites of A. nidulans. This confirmed that the fungal silent genes were induced to produce these compounds only in the presence of the bacterium in a co-culture, but not in a fungal mono-culture. Compared with a monoculture of Fusarium tricinctum, its co-culture with the bacterium Bacillus subtilis 168 trpC278 induced the production of three new secondary metabolites, macrocarpon C (15), N-(carboxymethyl)anthranilic acid (16), and (−)-citreoisocoumarinol (17), along with a 78-fold increase in the production of known fungal metabolites, including lateropyrone, fusaristatin, and enniatins A1, B, and B1 (Ola et al., 2013). Interestingly, compounds 15–17 were not detected when F. tricinctum was cocultured with S. lividans or in fungal and bacterial mono- cultures, confirming that expression of genes in F. tricinctum is enhanced only by B. subtilis specifically. Co-cultivation of the marine-derived fungus A. fumigatus and the marine-derived bacterium Sphingomonas sp. yielded a cytotoxic, antibacterial diketopiperazine disulfide: glionitrin A (18). This

Please cite this article as: Abdalla, M.A., et al., Microbial communication: A significant approach for new leads, South African Journal of Botany (2017), https://doi.org/10.1016/j.sajb.2017.10.001

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novel compound displayed strong cytotoxic and antibacterial activities (Table 1) (Park et al., 2009). Another study found that co-culturing Bacillus amyloliquefaciens GA40, a coral bacterium, with A. fumigatus and A. niger yielded antifungal metabolites related to the iturin family (Moree et al., 2013). The effect of bacterial cells and cell-free bacterial broth on the fungus Arthrinium c.f. saccharicola was studied, and the fungus was co-cultured with 14 different fouling bacterial taxa. Fungus growth was reduced during co-culturing with six bacteria, especially Pseudoalteromonas piscicida. A cell-free culture broth of P. piscicida improved the bioactivity of the fungus. The study concluded that the fungus may be able to deliver more bioactive compounds under stress conditions (Miao et al., 2006). Mixed fermentation of the fungus with bacteria increased the fungal bioactivity, which may be attributable to the secondary metabolites that are produced by the bacteria in the culture medium. The bacterial compounds may act as signaling molecules, which may contribute to the fungal bioactivity by inducing the fungal biosynthesis of antibacterial compounds (Miao et al., 2006). Co-cultivating the fungus Emericella sp., which was isolated from the surface of the marine green alga Halimeda sp., with the actinomycete Salinispora arenicola, which can be found in marine sediments, induced a 100-fold increase in production of the fungal depsipeptides emericellamides A (19) and B (20) (Oh et al., 2007). Both compounds exhibited modest antibacterial activities against methicillin-resistant Staphylococcus aureus (Oh et al., 2007). Fig. 2 shows examples of natural products reported from fungal-bacterial mixed fermentation. A study on the microbial interaction between Pseudomonas aeruginosa and A. fumigatus at the molecular level using matrixassisted laser desorption/ionization-imaging mass spectrometry (MALDI–IMS) combined with tandem mass spectrometry (MS/MS) characterized the secondary metabolites excreted by these microorganisms when grown on agar medium. It was indicated that the phenazine metabolites produced by P. aeruginosa were modified by A. fumigatus, enhancing their toxicity and capability to encourage fungal siderophore biosynthesis (Moree et al., 2012; Rutledge and Challis, 2015). The study reported that phenazine-1-carboxylic acid produced by P. aeruginosa was converted to 1-hydroxyphenanzine (21), 1-methoxyphenazine (22) and phenazine-1-sulfate (23) in the presence of A. fumigatus (Moree et al., 2012). The fungal siderophore triacetylfusarinine C was observed in MALDI-IMS as unbound, aluminum-chelated triacetylfusarinine C [Al3+] (24) and the iron-complexed form triacetylfusarinine C [Fe3+] (25). By using MALDI-IMS, siderophores were detected in the interaction zone between A. fumigatus and P. aeruginosa. The study reported that more Al3+-bound triacetylfusarinine C (24) and fusarinine C were found in comparison to the Fe3 + -chelated form (25). None of the metal-complexed or unbound siderophores has been detected in the MALDI-IMS or in the culture of the control fungus (Moree et al., 2012). Recently, fungal-bacterial co-culturing of A. niger and S. coelicolor delivered several compounds, including the cyclic dipeptide cyclo(PhePhe) and 2-hydroxyphenylacetic acid (Wu et al., 2015a). A recent report indicated that mixed fermentation of the endophytic fungus Chaetomium sp. with the bacterium Bacillus subtilis resulted in an up to 8.3-fold increase in the production of present metabolites (Akone et al., 2016). Moreover five new compounds named as shikimeran A (26), bipherin A (27) chorismeron (28), quinomeran (29) and serkydayn (30) were discovered only in the co-cultures and not in single fungal cultures. Compound 30 showed weak to moderate activity against B. subtilis while other compounds were inactive (minimum inhibitory concentration or MIC N 100 μM) (Table 1) (Akone et al., 2016). 2.2. Bacterial-bacterial co-cultures and their potential to induce secondary metabolite biosynthesis Bacterial-bacterial interactions have been investigated for a long time, ever since competition between Streptomyces dusseldorf,

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S. lividans TK24, and S. bikiniensis ATCC 11062 in soil was detected (Turpin et al., 1992). The survival of S. dusseldorf was induced by S. lividans in sterile, improved soil, while its survival was inhibited by the presence of the known streptomycin producer S. bikiniensis (Turpin et al., 1992). During mixed fermentation of S. lividans TK23 with mycolic acid-containing bacterium Tsukamurella pulmonis TP-B0596, a red pigment was observed. The induction of two red pigments by S. lividans TK23 was studied under certain conditions as an indicator of secondary metabolites production (Onaka et al., 2011). The co-cultivation of Streptomyces endus S-522 and T. pulmonis TP-B0596 produced a potential antibiotic, alchivemycin A (31) (Onaka et al., 2011). The marine-derived bacterium Streptomyces tenjimariensis delivered the antibiotics istamycins A (32) and B (33) (Slattery et al., 2001). Co-cultivation experiments have been performed to test the influence of mixed fermentation of marine bacteria on the production of istamycin by S. tenjimariensis (Slattery et al., 2001). This study reported that 12 of 53 bacterial species tested (22.6%) activated istamycin production by 2-fold more than its production by S. tenjimariensis mono-culture. In addition, the istamycin antibiotic suppressed the growth of the competitor colonies (Slattery et al., 2001). Recently, unique secondary metabolites have been reported from co-culturing Streptomyces coelicolor with five actinomycetes (Traxler et al., 2013). To detect these metabolites, two techniques were combined: nanospray desorption electrospray ionization (Nano-DESI) and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) imaging mass spectrometry (IMS) (Moree et al., 2012, 2013; Traxler et al., 2013). During various bacterial-bacterial interactions, spectral networking yielded a family of unidentified secondary metabolites obtained from S. coelicolor. At least 12 desferrioxamines with acyl side chains of various lengths were produced. The compounds were induced by siderophores produced by neighboring strains. The results indicated that interactions among actinomycete bacteria result in a wide range of production of secondary metabolites, with high complexity and specificity (Traxler et al., 2013). The spectral network obtained by NanoDESI and MALDI-TOF imaging analyses delivered 629 compounds. Importantly, many of these metabolites were unknown. Interestingly, the molecules associated with S. coelicolor colonies in the interaction of S. coelicolor with five actinomycetes changed from interaction to interaction hypothesizing a response in each case. Various interactions stimulated production of an extended family of acyl-desferrioxamine siderophores, which have never been isolated from S. coelicolor (Traxler et al., 2013). S. griseus and S. coelicolor, which are known as antibiotic-producing soil bacteria, were co-cultivated with B. subtilis in three different experiments. The aim of the study was to examine the role of antibiotics in three different competitions. B. subtilis was laid out in a growth medium and consequently inoculated with one of the two Streptomyces spp. The second experiment was co-cultivation of B. subtilis and a chosen Streptomyces strain. In the third competition experiment Streptomyces sp. was established first then B. subtilis was inoculated later. The results showed that antibiotic production reduced invasion by competitors, where the two Streptomyces spp. inhibited invasion by B. subtilis. No advantage for the streptomycetes has been detected over the existing population of B. subtilis (Wiener, 1996). Mixed fermentation of Actinokineospora sp. EG49 and Nocardiopsis sp. RV163 activated the biosynthetic pathways of three metabolites that were not found in mono-cultures of either microorganism. The compounds were identified as N-(2-hydroxyphenyl)-acetamide (34), 1,6-dihydroxyphenazine (35), and 5a,6,11a,12-tetrahydro-5a,11a– dimethyl[1,4]benzoxazino[3,2-b][1,4]benzoxazine (36a) and 2,2′,3,3′tetrahydro-2,2′-dimethyl-2,2′-bibenzoxazole (36b). Compound 35 displayed biological activity against Bacillus sp. P25, Trypanosoma brucei, and Actinokineospora sp. EG49 (Dashti et al., 2014). Recently arcyriaflavin E (37), a new cytotoxic indolocarbazole alkaloid, was discovered in a coculture of S. cinnamoneus NBRC 13823 with T. pulmonis (Hoshino et al., 2015a). Niizalactams A–C (38–40) were obtained by mixed fermentation

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Co-culture combination

Bioactive compounds induced by co-culture

Biological significance of induced compounds

Reference

Marine fungus Pestalotia and marine bacterium alphaproteobacterium CNJ-328

Pestalone (1)

Cueto et al. (2001)

Marine bacterium α-proteobacterium (Strain CNJ-328) and marine-derived fungus Libertella sp.

Libertellenones A–D (2–5)

Aspergillus fumigatus with Streptomyces peucetius

Fumiformamide (6) N,N′-(1Z,3Z)-1,4-bis(4-methoxyphenyl)buta1,3-diene-2,3-diyl)diformamide (7) Glionitrin A (18)

Compound 1 displayed moderately interesting antimicrobial activity against methicillin-resistant Staphylococcus aureus (the minimum inhibitory concentration, MIC = 37 ng/mL) and against vancomycin-resistant Enterococcus faecium (MIC = 78 ng/mL). In addition, it showed in vitro cytotoxicity in the National Cancer Institute's 60 Human Tumor Cell Line Screen (mean 50% Growth Inhibition, GI50 = 6.0 μM) Compounds 2–5 exhibited weak activity (MIC N 160 μg/mL) against Candida albicans. However, libertellenone D (5) possessed potent cytotoxicity (IC50 = 0.76 μM) against the HCT-116 Human Colon Carcinoma cancer cell line. Libertellenones A–C (2–4) showed less cytotoxicity (IC50 = 15, 15, and 53 μM, respectively) Compound 7 displayed strong cytotoxic activity against several cell lines ▪ Strong cytotoxic activity against HCT-116, A549, AGS, and DU145 cells (IC50 = 0.82, 0.55, 0.45, and 0.24 μM, respectively) ▪ Antibacterial activity against MRSA (MIC 0.78 μg/mL) Antifungal activity Modest antibacterial activities against methicillin-resistant Staphylococcus aureus (MIC 3.8 and 6.0 μM, respectively) As reported by Moree et al. (2012) 1-hydroxyphenanzine (21) and 1-methoxyphenazine (22) suppressed fungal growth, while compound 23 did not. The siderophores triacetylfusarinine C, triacetylfusarinine C [Al3+] (24) and triacetylfusarinine C [Fe3+] (25) are well-known to stimulate the capturing of iron, which needed for a number of cellular processes (Renshaw et al., 2002). Aluminum can also form complexes with siderophores because it has similar charge and size as iron (Evers et al., 1989). Aluminum is also known to be toxic to many organisms and can enhance siderophore production like iron (Hu and Boyer, 1996). Accordingly, fusarinines may act as protective compounds by chelating aluminum in extracellular compartment (Renshaw et al., 2002) Compound 30 demonstrated weak to moderate activity against B. subtilis with a MIC value of 53 μM, while other compounds were inactive (MIC N100 μM). Moreover, compound 30 exhibited the strongest activity among all tested compounds against the growth of the mouse lymphoma L5178Y cell line with an IC50 value of 1 μM. Compound 29 showed weak cytotoxicity with IC50 values of 38.6 μM

Park et al. (2009)

Marine-derived fungus Aspergillus fumigatus and the marine-derived bacterium Sphingomonas sp. B. amyloliquefaciens GA40, A. fumigatus and A. niger Emericella sp. and actinomycete Salinispora arenicola

Metabolites belong to the iturin family Depsipeptides emericellamides A (19) and B (20)

A. fumigatus and P. aeruginosa

1-Hydroxyphenanzine (21) 1-methoxyphenazine (22), phenazine-1-sulfate (23) triacetylfusarinine C [Al3+] (24) and triacetylfusarinine C [Fe3+] (25).

Endophytic fungus Chaetomium sp. and Bacillus subtilis

Five new compounds named as shikimeran A (26), bipherin A (27) chorismeron (28), quinomeran (29) and serkydayn (30)

Oh et al. (2005)

Zuck et al. (2011)

Moree et al. (2013) Oh et al. (2007) Moree et al. (2012)

Akone et al. (2016)

M.A. Abdalla et al. / South African Journal of Botany xxx (2017) xxx–xxx

Please cite this article as: Abdalla, M.A., et al., Microbial communication: A significant approach for new leads, South African Journal of Botany (2017), https://doi.org/10.1016/j.sajb.2017.10.001

Table 1 Important bioactive compounds induced by mixed fermentation and their biological importance.

Streptomyces cinnamoneus NBRC 13823 with Tsukamurella pulmonis Streptomyces sp. NZ-6 with the mycolic acid containing bacterium Tsukamurella pulmonis TP-B0596 Streptomyces sp. CJ-5, with the mycolic acid-containing bacterium Tsukamurella pulmonis TP-B0596.

Alchivemycin A (31)

Onaka et al. (2011)

Istamycins A (32) and B (33)

Potent antibiotics Compounds 32 and 33 inhibited the growth of the competitor Slattery et al. (2001) colonies N-(2-hydroxyphenyl)-acetamide (34), 1,6-dihydroxyphenazine (35), Compound 35 possessed biological activity against Bacillus sp. P25, Trypanosoma brucei, Dashti et al. (2014) and Actinokineospora sp. EG49 and 5a,6,11a,12-tetrahydro-5a,11a–dimethyl[1,4]benzoxazino[3,2b][1,4]benzoxazine (36a) and 2,2′,3,3′-tetrahydro-2,2′-dimethyl-2,2′bibenzoxazole (36b) Arcyriaflavin E (37) Exhibited cytotoxic activity with IC50 of 39 μM against P388 murine leukemia cells Hoshino et al. (2015a) Niizalactams A–C (38–40)

None of the compounds had any antimicrobial activities or cytotoxicities

Hoshino et al. (2015b)

Chojalactones A–C (41–43)

Compounds 41 and 42 displayed moderate cytotoxicity against P388 murine leukemia cells in methylthiazole tetrazolium (MTT) assays. The IC50 values for 41 and 42 were 28 and 18 μM respectively Cytotoxic activity against P388, PXPC-3, MCF-7, CNS SF268, NSC H460, KM20L2, and DU-145 tumor cells, with IC50 values of from 1.7–2.0 μM. In addition to antimicrobial activity against C. albicans, Micrococcus luteus, S. aureus, E. faecalis, and S. pneumoniae, with MIC values from 2 to 16 μg/mL Compounds 44 and 45 were inactive in cytotoxic and antibacterial assays

Hoshino et al. (2015c)

Dihydrofarnesol, with more potent antifungal activity than that of fluconazole, a frontline clinical antifungal agent Displayed significant inhibitory activity against three Gram-positive bacteria, S. aureus, S. epidermidis, and B. subtilis, with IC50 values of 62.50, 31.25 and 15.62 μg/mL respectively and three Gram-negative bacteria, B. dysenteriae, B. proteus, and E. coli with IC50 values of 15.62, 62.50 and 31.25 μg/mL respectively Compound 48 was found to be inactive in brine shrimp lethality and antibacterial activity assays Not reported Compounds 51and 52 exhibited weak activity against Vibrio alginolyticus, with MIC value of 16.0 μg/mL

Brasch et al. (2014)

Five sediment-derived fungi; Oyadendron sulphureoochraceum, Ascochyta pisi, Emercillopsis minima, Cylindrocarpon destructans, and Fusarium oxysporum

Lateritin

Plant endophytic fungi Fusarium tricinctum and Fusarium begonia Candida albicans with skin-commensal fungi, including Trichophyton rubrum Two epiphytic fungi belonging to the genus Aspergillus

Depsipeptides subenniatins A (44) and B (45)

Soil-derived fungi Penicillium pinophilum and Trichoderma harzianum Trichophyton rubrum and Bionectria ochroleuca Marine-derived fungal isolates of Penicillium citrinum and Beauveria felina.

Potent antibiotic activity against Micrococcus luteus at a concentration of 0.06 μg/ml

Dihydrofarnesol (46) and farnesol Aspergicin (47) along with the known metabolites neoaspergillic acid and ergosterol

A new compound secopenicillide C (48) along with penicillide, MC-141, stromemycin, and pestalasin A 4-Hydroxysulfoxy-2,2-dimethylthielavin P (49) Citrifelins A (51) and B (52),

Pettit et al. (2010)

Wang et al. (2013)

Zhu et al. (2011)

Nonaka et al. (2011) Bertrand et al. (2013) Meng et al. (2015)

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Please cite this article as: Abdalla, M.A., et al., Microbial communication: A significant approach for new leads, South African Journal of Botany (2017), https://doi.org/10.1016/j.sajb.2017.10.001

Streptomyces endus S-522 and Tsukamurella pulmonis TP-B0596 or Corynebacterium glutamicum Co-cultivation of S. tenjimariensis with twelve bacterial species Actinokineospora sp. EG49 and Nocardiopsis sp. RV163

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6

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Fig. 2. Natural products reported from fungal-bacterial mixed fermentation.

of Streptomyces sp. NZ-6 with the mycolic acid-containing bacterium T. pulmonis TP-B0596 (Hoshino et al., 2015b). Co-cultivation of Streptomyces sp. CJ-5 and the mycolic acid-containing bacterium Tsukamurella

pulmonis TP-B0596 afforded also chojalactones A–C (41–43) (Hoshino et al., 2015c). Fig. 3 shows some of the natural products that have been reported from bacterial-bacterial mixed fermentation.

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Fig. 3. Natural products reported from bacterial-bacterial mixed fermentation.

2.3. Fungal-fungal co-cultures and their role in producing secondary metabolites Mixed fermentation of five sediment-derived fungi, including Oyadendron sulphureoochraceum, Ascochyta pisi, Emercillopsis minima, Cylindrocarpon destructans and Fusarium oxysporum, yielded lateritin, which displayed cytotoxic activity against P388, PXPC-3, MCF-7, CNS SF268, NSC H460, KM20L2 and DU-145 tumor cells, with IC50 values from 1.7–2.0 μM (Pettit et al., 2010). In addition, lateritin displayed antimicrobial activity against C. albicans, Micrococcus luteus, S. aureus, E. faecalis and Streptococcus pneumoniae, with MIC values from 2 to 16 μg/mL (Pettit et al., 2010). Co-cultivation of the plant endophytic fungi Fusarium tricinctum and Fusarium begonia produced the new linear depsipeptides subenniatins A (44) and B (45), along with the known cyclic depsipeptides enniatins A, A1, B, and B1, which have previously been reported as being produced by F. tricinctum (Wang et al., 2013). Recently, Candida albicans was investigated and found to deliver a number of novel volatile compounds, including dihydrofarnesol (46) and farnesol, when co-cultured with other common, skin-commensal fungi, including Trichophyton rubrum (Brasch et al., 2014). Dihydrofarnesol (46) was produced only in the presence of T. rubrum and exhibited antifungal activity that was more potent than that of fluconazole, a frontline, clinical antifungal agent (Brasch et al., 2014). Two epiphytic fungi belonging to the genus Aspergillus and derived from mangroves were co-cultured to deliver a new alkaloid, aspergicin (47), along with the known metabolites neoaspergillic acid and ergosterol (Zhu et al., 2011). Co-culturing Trametes versicolor, Bjerkandera adusta and Hypholoma fasciculare yielded significant variations in the

production of metabolites. Production seemed to be limited to the interaction zone between T. versicolor and its fungal competitor, highlighting that close intimacy between mycelia plays a significant role in changing the expression patterns of biosynthetic pathways (Eyre et al., 2010). T. versicolor is a known producer of pharmaceutically important metabolites, including protein-bound polysaccharide-K (PSK), a potent antitumor and anti-HIV polysaccharide, and protein-bound polysaccharideP (PSP), an immune modulator (Zjawiony, 2004; Eyre et al., 2010). A co-culture of the soil-derived fungi Penicillium pinophilum and Trichoderma harzianum delivered a new natural product, secopenicillide C (48), as well as penicillide, MC-141, stromemycin, and pestalasin A (Nonaka et al., 2011). Compound 48 was found to be inactive in the brine shrimp lethality and antibacterial activity assays (Xu, 2015). Co-cultivation of Trichophyton rubrum and Bionectria ochroleuca displayed an interesting, long-distance growth inhibition between the two fungi. A new compound was identified as 4-hydroxysulfoxy-2,2dimethylthielavin P (49), a substituted trimer of 3,5-dimethylorsellinic acid. A non-sulfated compound, PS-990 (50), and other known metabolites were obtained from mono-culturing the fungus B. ochroleuca (Bertrand et al., 2013). No activity has been reported for compound 49 in this study. In addition, compound 49 was obtained from this coculture, while its non-sulfated form, PS-990 (50), was found in monocultures of both fungal strains. Compound 49 could be delivered by either of these two strains (Mier, 1957; Blank et al., 1963; Ikuta et al., 1997; Gupta et al., 2000; Freinkman et al., 2009; Ebrahim et al., 2012). Citrifelins A (51) and B (52) were obtained from co-culture of marinederived fungal isolates of Penicillium citrinum and Beauveria felina (Meng et al., 2015). These fungi did not deliver these compounds

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Fig. 4. Natural products reported from fungal-fungal co-cultures.

when in single culture. Fig. 4 shows some of the natural products that have been reported from fungal-fungal co-cultures. 3. Biological importance of microbial co-culture Natural products promoted by co-cultivation of multiple microorganisms provide evidence that co-culture is an extremely promising means of enhancing the biosynthesis of bioactive metabolites which are not found during mono-culture (Ueda and Beppu, 2017). Coculture tactics may offer new drug candidates as indicated by many mixed fermentation experiments (Marmann et al., 2014). An example is the study of the antagonistic response of marine bacteria which was revealed in an interaction with terrestrial bacteria. The study suggested that the capability of marine epibiotic bacteria to afford numerous

antibiotic candidates could be triggered by an antagonistic interaction with the cells of pathogenic bacteria, and in this way antimicrobial drugs could be produced (Burgess et al., 1999). Table 1 summarizes important bioactive compounds induced to date through the microbial cocultivation approach, and their medicinal importance. 4. Analytical methods used to identify natural products induced by co-culture Following mixed fermentation, an important step is the challenge to identify and compare the metabolites from mono- and co-culture supernatants. One of the important tools used to accomplish this is High Performance Liquid Chromatography (HPLC), which affords the capability of monitoring the changes between various chromatograms of

Fig. 5. Various techniques for identifying metabolites from microbial co-cultures.

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mono- and co-cultures to detect changes in the metabolic profiles (Rutledge and Challis, 2015). In this case, metabolites, which should be expected in the co-culture fluid, could easily be identified. To improve purification of the compounds induced by co-culture, chromatographic techniques, including semi-preparative HPLC, Counter-Current Chromatography (CCC), Over-Pressured Layer Chromatography (OPLC) and Preparative Thin-layer Chromatography (PTLC), can be used for purifying metabolites in sufficient quantities for structural analysis (Klebovich et al., 1998; Mincsovics et al., 2013; Do et al., 2014). In a previous study software-oriented semi-preparative HPLCMS was successfully used to purify compounds induced by fungal coculture (Bertrand et al., 2013). Techniques such as Nano-Electrospray Ionization (nanoESI) (Schmidt et al., 2003) and Chip-Based nanoESI have shown great progress in the identification of metabolites, which vary extremely among extracts (Lazar et al., 2006; Wickremsinhe et al., 2006; Pereira-Medrano et al., 2007; Almeida et al., 2008; Lydic et al., 2009). Another efficient technique recently applied to detect metabolites from co-culture is Ultra-High Pressure Liquid Chromatography Time of Flight (UHPLC-TOF) coupled to a micro-TOF-2Q mass spectrometer (MS) with an ESI interface. Metabolites of interest can easily be detected in both positive and negative ion modes (Wu et al., 2015a,b). Recently, great achievements have been made in this context using MALDI–IMS. Secondary metabolites produced by one microorganism in response to another can be identified using MALDI–IMS (Moree et al., 2012, 2013; Rutledge and Challis, 2015). The interesting interactions between P. aeruginosa and A. fumigatus and identification of compounds in microbial extracts have been discovered using MALDI-TOF and MALDI-FT-ICR imaging mass spectrometry (MALDI-IMS), combined with MS/MS networking (Moree et al., 2012, 2013). A powerful technique for characterization of metabolites in microbial co-culture and complex mixtures is Nuclear Magnetic Resonance (NMR) spectroscopy based metabolomics coupled with multivariate data analysis (Wu et al., 2015a,b). This technique aids direct biochemical analysis of the metabolites (Kim et al., 2010). Pure compounds obtained by microbial coculture can be identified by applying further spectroscopic techniques, such as NMR spectroscopy. Various 1D and 2D experiments can be used with modern, high-resolution NMR spectrometers (Simpson, 2011). Cryogenically cooled NMR probes offer advantages in measuring samples as small as tens of micrograms of purified substance (Simpson, 2011). In addition, X-ray crystallography can be used if sufficient crystals are available. Fig. 5 illustrates important techniques for identifying metabolites from microbial co-cultures. 5. Conclusion Microbial co-culturing has the capacity to produce numerous novel metabolites with a wide range of interesting bioactivities. In their natural habitats, it can be assumed that during microbial interaction, competitors or symbionts trigger the biosynthetic pathways of novel metabolites and induce chemical diversity (Kusari et al., 2012). Several bioactive compounds were discovered from microbial co-culture indicating that this approach offers promising conditions for secondary metabolite production. On the other hand numerous substances whose production is increased by the antagonistic interaction of different microorganisms have been reported, such as emericellamide A (19) and B (20) and istamycins A and B. By using interesting advanced techniques, such as Nano-DESI and MALDI-TOF IMS, secondary metabolites induced by co-cultures have been widely investigated. Microbial interactions and their novel molecules were easily detected by analyzing spectral networking. Importantly, these complementary technologies afforded investigation of the produced metabolites directly from the microorganism colonies (Traxler et al., 2013). High-resolution UHPLCTOF-MS profiles were very helpful in identifying metabolites present in co-culture extracts (Wu et al., 2015a,b). To date, few co-culturing experiments have confirmed the activation of natural product gene clusters as a response to neighboring microorganisms. It is noteworthy

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that discovered bioactive compounds whose production was minimal under the normal mono-cultivation conditions could be enhanced by co-cultivation. It is crucial to understand the diversity and complexity of the interesting interaction and chemical communication among microorganisms to perform successful co-culturing experiments.

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Please cite this article as: Abdalla, M.A., et al., Microbial communication: A significant approach for new leads, South African Journal of Botany (2017), https://doi.org/10.1016/j.sajb.2017.10.001