Bacteria of the Genus Xenorhabdus, a Novel Source of Bioactive Compounds

fmicb-09-03177 December 17, 2018 Time: 17:4 # 1 REVIEW published: 19 December 2018 doi: 10.3389/fmicb.2018.03177 Bacteria of the Genus Xenorhabdus, a Novel Source of Bioactive Compounds Jönike Dreyer1, Antoinette P. Malan2 and Leon M. T. Dicks1* 1 Department of Microbiology, Stellenbosch University, Stellenbosch, South Africa, 2 Department of Conservation Ecology and Entomology, Stellenbosch University, Stellenbosch, South Africa The genus Xenorhabdus of the family Enterobacteriaceae, are mutualistically associated with entomopathogenic nematodes of the genus Steinernema. Although most of the associations are species-specific, a specific Xenorhabdus sp. may infect more than one Steinernema sp. During the Xenorhabdus–Steinernema life cycle, insect larvae are infected and killed, while both mutualists produce bioactive compounds. These compounds act synergistically to ensure reproduction and proliferation of the nematodes and bacteria. A single strain of Xenorhabdus may produce a variety of antibacterial and antifungal compounds, some of which are also active against Edited by: insects, nematodes, protozoa, and cancer cells. Antimicrobial compounds produced by Santi M. Mandal, Indian Institute of Technology Xenorhabdus spp. have not been researched to the same extent as other soil bacteria Kharagpur, India and they may hold the answer to novel antibacterial and antifungal compounds. This Reviewed by: review summarizes the bioactive secondary metabolites produced by Xenorhabdus spp. Prabuddha Dey, and their application in disease control. Gene regulation and increasing the production Rutgers University – The State University of New Jersey, of a few of these antimicrobial compounds are discussed. Aspects limiting future United States development of these novel bioactive compounds are also pointed out. Ekramul Islam, University of Kalyani, India Keywords: Xenorhabdus, bioactive compounds, secondary metabolites, antimicrobial properties, antimicrobial peptides *Correspondence: Leon M. T. Dicks [email protected] INTRODUCTION Specialty section: This article was submitted to Since the discovery of penicillin in 1928 and the introduction of sulphonamides in 1935, more than Antimicrobials, Resistance 20 classes of antibiotics entered the market (Coates et al., 2002; Powers, 2004). The majority of and Chemotherapy, these antibiotics were developed between 1940 and 1962 (Coates et al., 2011). No novel classes of a section of the journal antibiotics were developed between 1968 and 1998. Antibiotics developed up to 1960 protected Frontiers in Microbiology humans from infections for approximately 50 years (Coates et al., 2011). Within 2 years of Received: 18 June 2018 marketing, resistance is usually observed, even to new classes of compounds (Bax et al., 1998). Accepted: 07 December 2018 With the current rate at which bacteria develop resistance, we may need more than 20 new classes Published: 19 December 2018 of antibiotics to last us for the next 50 years (thus up to 2060). Citation: Infections caused by Gram-negative bacteria are difficult to treat and many produce metallo- Dreyer J, Malan AP and b-lactamase that neutralize carbapenems (Kumarasamy et al., 2010). Strains of Staphylococcus Dicks LMT (2018) Bacteria of the Genus Xenorhabdus, a Novel Source aureus developed resistance to penicillin in the early 1940s, shortly after its introduction into the of Bioactive Compounds. market (Chambers and Deleo, 2009). Resistance to methicillin was recorded just 1 year after its Front. Microbiol. 9:3177. introduction. Nowadays, most of the deaths caused by S. aureus are due to MRSA (Klein et al., doi: 10.3389/fmicb.2018.03177 2007). Other pathogens in the so-called ESKAPE group for which new antibiotics are urgently Frontiers in Microbiology| www.frontiersin.org 1 December 2018| Volume 9| Article 3177 fmicb-09-03177 December 17, 2018 Time: 17:4 # 2 Dreyer et al. Xenorhabdus, a Novel Source of Bioactive Compounds needed are Enterococcus faecium, Acinetobacter baumanii, synthetases (NRPS) are responsible for the production of a Klebsiella pneumoniae, Pseudomonas aeruginosa, and diverse group of peptides, e.g., depsipeptides (Lang et al., 2008; Enterobacter species (Rice, 2010). Zhou et al., 2013; Kronenwerth et al., 2014), xenocoumacins Another emerging pathogen is Clostridium difficile. Infections (Reimer, 2013), and PAX (peptide-antimicrobial-Xenorhabdus) caused by C. difficile increased dramatically over the last peptides (Fuchs et al., 2011). Other Xenorhabdus antimicrobial decade, especially in patients with irritable bowel disease (IBD) compounds include benzylideneacetone (Ji et al., 2004), indole (Nguyen et al., 2008). Severe cases of CDI are treated with oral derivatives (Sundar and Chang, 1993), and ribosomal-encoded metronidazole (250–500 mg four times a day for 10–14 days), or bacteriocins (Thaler et al., 1995; Singh and Banerjee, 2008). oral vancomycin (125–500 mg four times a day for 10–14 days). The Steinernema life cycle is shown in Figure 1. Phase I cells Metronidazole is often administered intravenously, in doses of of Xenorhabdus are associated with reproducing nematodes, but 500 mg four times daily (Persky and Brandt, 2000). Although changes to phase II when nematodes infect the insect cadaver metronidazole is the antibiotic of choice, failure rates of 22 to 38% (Akhurst, 1980). Phase I cells are larger than phase II cells, have been reported and many strains have developed resistance have crystalline inclusion bodies, are mobile (by swarming), and (Miller et al., 2010, 2011). produce proteases, lipases, and bioactive compounds (Akhurst, The rate at which bacteria develop resistance to antibiotics 1982; Boemare and Akhurst, 1988). The two phases are depends on the genetic characteristics of the pathogen and the clearly distinguished by staining with bromothymol blue and mode of action of the antibiotic. For instance, resistance to triphenyltetrazolium chloride (Kaya and Stock, 1997). Phase rifampicin, which inhibits DNA-dependent RNA polymerase, I cells streaked onto growth media supplemented with a develops much faster than resistance to antibiotics that target cell combination of the two dyes form dark blue colonies with a membranes (Lambert, 2005; Zhanel et al., 2008). Bacteria have red core and are surrounded by a clear zone. Exceptions to several mechanisms to protect themselves against antibiotics, e.g., the rule have been reported, i.e., phase I cells not absorbing (i) inactivation of the antibiotic (e.g., production of b-lactamase bromothymol blue (Koppenhöfer, 2007). Nematodes infected degrading the b-lactam ring in penicillins and cephalosporins), with Xenorhabdus enter the insect host through natural openings, (ii) changing membrane permeability to reduce the uptake of an such as the mouth, anus and respiratory spiracles, and migrates antibiotic, (iii) changing efflux pumps to increase the excretion of to the hemocoel. Once in the hemocoel, the nematodes enter an antibiotic from the cell, (iv) increasing production of the target a feeding phase, whereupon the bacteria are released (by enzyme, (v) finding alternative mechanisms to bypass damaged defecation) and start to produce compounds to repress the cell components, and (vi) altering the target site to render the insect’s immune system (Webster et al., 2002). The protein antibiotic ineffective. Some antibiotics, such as fluoroquinolones, UnA, produced by some strains of Xenorhabdus nematophila, induce the SOS response in cells, which increases the level of prevents the hemocytes of the insect to aggregate and form errors in DNA replication and by doing so, increases resistance (Da Re et al., 2009). It is evident that we need novel antibiotics to treat bacterial infections. Oxazolidinone (linezolid by Pfizer) and cyclic lipopeptide (daptomycin by Cubist), with activity against Gram-positive bacteria, including MRSA, are two of the most recent antibiotics released into the market (Coates et al., 2011). There may be a number of yet to be published antibiotics that are currently in preclinical development, but the overall conclusion is that we are heading for a disaster if antibiotics with broader antimicrobial activity are not developed in the next few years. The rate at which novel antibiotics are being developed is just not sufficient to control bacterial infections. We need to focus our efforts in developing antibiotics that target complex bacterial systems, such as cell membranes. Xenorhabdus spp. produce various bioactive compounds throughout their life cycle and the genus is an underestimated and neglected source of novel bioactive compounds. All strains live in close association with entomopathogenic nematodes (EPNs) of the family Steinernematidae. Biologically active FIGURE 1 | The Steinernema life cycle. The infective juvenile (IJ) nematodes infect an insect host and recover to the feeding phase (J3). J3 nematodes compounds produced by Xenorhabdus spp. have a broad- molt into fourth phase (J4) juveniles, which in turn develop into male and spectrum of antimicrobial activity, inhibiting the growth of female adults. These adults reproduce and lay eggs. The eggs hatch as first bacteria, fungi and protozoa, the development of insects and phase juveniles (J1) which feed and molt to second, third, and fourth juvenile nematodes, and the formation of cancerous cells (Webster phases (J2–J4), and ultimately into adults. After one to three generations, et al., 2002). The variety of bioactive compounds produced when nutrients are depleted, second phase juveniles develop into IJs (special

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