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Crit Rev Microbiol, Early Online: 1–14 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/1040841X.2013.875982

REVIEW ARTICLE Antibiotrophs: The complexity of antibiotic-subsisting and antibiotic-resistant microorganisms

Yvon Woappi1, Prashant Gabani1, Arya Singh2, and Om V. Singh1

1Division of Biological and Health Sciences, University of Pittsburgh, Bradford, PA, USA and 2Department of Computer Science, Texas State University, San Marcos, TX, USA

Abstract Keywords Widespread overuse of antibiotics has led to the emergence of numerous antibiotic-resistant Antibiotic-production, antibiotic-resistance, bacteria; among these are antibiotic-subsisting strains capable of surviving in environments antibiotic-subsistence, antibiotrophs, with antibiotics as the sole carbon source. This unparalleled expansion of antibiotic resistance extremophiles, gene-transfer, multi-drug reveals the potent and diversified resistance abilities of certain bacterial strains. Moreover, resistance, systems biology these strains often possess hypermutator phenotypes and virulence transmissibility competent for genomic and proteomic propagation and pathogenicity. Pragmatic and prospicient History approaches will be necessary to develop efficient therapeutic methods against such bacteria and to understand the extent of their genomic adaptability. This review aims to reveal the Received 1 October 2013 niches of these antibiotic-catabolizing microbes and assesses the underlying factors linking Revised 6 December 2013 natural microbial antibiotic production, multidrug resistance, and antibiotic-subsistence. Accepted 12 December 2013 Published online 4 February 2014

Introduction antibiotics, and the molecular genetics of the respective microorganisms have been well studied over the years Bacterial survival has been optimized by fast reproduction (Helling et al., 2002; Nikaido, 2009). However, the metab- cycles, frequent genomic interchange and swift metabolic

For personal use only. olism of unmetabolized drugs from the extensive use of adaptability. This metabolic flexibility can trigger the forma- antibiotics in humans and animals has yet to be understood. tion of secondary metabolites (e.g. antibiotics and toxins) that Prolonged exposure to residual antibiotics under both in vivo are not essential for the growth and reproduction of the and in vitro conditions produces microorganisms that, under organisms that produce them. An antibiotic has been defined selective pressure, evolve into AREs (Gabani et al., 2012). as an organic compound produced by one microorganism to Antibiotic resistance in bacteria could be defined as the inhibit the growth of another; however, this definition does not microbial ability to sustain and multiply in the presence of reflect non-microbial sources (e.g. plants). For any one antibiotics (Aminov & Mackie, 2007), which has raised antibiotic, there is a specific group of microorganisms global concern due to its devastating impacts, such as spread comprising its inhibition spectrum, meaning they are sensitive of infections across continents and prolonged illness. The to the antibiotic at therapeutically possible dosage levels rapidity with which many resistances have appeared after the (Canton & Morosini, 2011). However, the most common introduction of new antibiotics suggests that resistance genes antibiotics and respective microorganisms (i.e. bacteria and were already present in nature prior to human use of fungi) in nature, as summarized in Table 1, may enforce long- antibiotics. Exclusively antibiotic-resistant strains have been Critical Reviews in Microbiology Downloaded from informahealthcare.com by University of South Carolina on 05/29/15 term selective pressure for the emergence of resistance, identified and their swift resistance adaptation patterns have generating another branch of extremophiles – antibiotic- been strongly linked to horizontal gene transfer (HGT) resistant extremophiles (ARE) (Gabani et al., 2012; Hawkey (Canton & Morosini, 2011; Liebert et al., 1999). The & Jones, 2009; Helling et al., 2002; Kajander & Ciftcioglu, intensifying relevance of resistant pathogens has, however, 1999; Nikaido, 2009). refocused contemporary studies toward resistance mechan- The bacterial spectrum can be divided into five central isms, leaving a relatively small amount of research investigat- metabolic groupings: (i) antibiotic producers, (ii) antibiotic- ing natural antibiotic production and its links to evolving resistant, (iii) both antibiotic producer and resistant, (iv) non- intercellular communication toward resistance (Martin et al., resistant, and (v) non-antibiotic-producing. The cellular 2005). Hence, an understanding of antibiotic production mechanisms for biosynthesis of secondary metabolites, i.e. and resistance acquisition is more relevant today than ever before. Over the past several decades, the methods of pathogenic Address for correspondence: Om V. Singh, University of Pittsburgh, Divison of Biological and Health Sciences, 300 Campus Drive, eradication have proven largely inefficient and unrealistic. Bradford, PA 16701 USA. E-mail: [email protected], [email protected] In fact, they have promoted microbial propagation and have 2 Y. Woappi et al. Crit Rev Microbiol, Early Online: 1–14

Table 1. Biosynthesis of secondary metabolites, i.e. antibiotics, in most common bacterial and fungal origin*.

Secondary metabolites Secondary metabolites Bacterial origin (i.e. antibiotics) Fungal origin (i.e. antibiotics) Amycolatopsis lactamdurans Cephamycin C Cephalosorium acremonium Cephalosporin C Bacillus licheniformic Bacitracin Penicillium chrysogenum, Penicillins, Griseofulvin, Patulin, P. griseofulvin, P. urticae respectively. Bacillus subtillis Bacillin, Subtillin Aspergillus nidulans Penicillin Erwinia chrysanthemi (Dickeya dadantii) Indigoidine Acremonium chrysogenum Cephalosporin Lysobacter lactamgenus Cephabacin Cercospora kikuchii Cercosporin Micromonospora sp. Micromonosorin Cochliobolus carbonum HC-toxin Nocardia uniformis Nocardicin A Pseudallescheria boydii Pseudallin Pseudomonas aureofaciens Pyrrolnitrin Mucor ramannianus Ramycin Streptomyces antibioticus Actinomycin, Oleandomycin Carpenteles brefeldianum Griseofulvin Streptomyces griseus Indolmycin, Streptomycin, Cordyceps militaris Cordycepin Candicidin Streptomyces kanamyceticus Kanamycin Giberella baccata Baccatin A Streptomyces fradiae Neomycin Nectria radicicola, Monosporium Radicicol bonorden Streptomyces albinogen Puromycin Chaetomium aureum, C. trilaterale Oosporein Streptomyces sioyaensis Siomycin C. cochliodes Chetomin, Orsenillic acid Streptomyces lavendulae Streptothricin Edothia parasitica Diaporthin Streptomyces cinnamonesis Monensin Neurospora crassa Spermine Streptomyces veneguelae Chloramphenicol Lambertela corni-maris, L. Lambertellin hicoriae Streptomyces verticillatus Mitomycin Mollisia caesia, M. gallens Mollisin Streptomyces caelestis Celesticetin Blennoria sp. Citrinin Streptomyces cacaoi Polyonins L & M Pestalotia ramulosa Ramulosin Streptomyces spinosus Spinosad Candida albicans Mycobacillin Streptomyces hygnoscopicus Rapamycin Achorion gypseum Achoricine Streptomyces pencetius Avermectin Aspergillus giganteus Alpha-Sarcin Streptomyces erythrea Erythromycin A. amstelodami, A. proliferans, A. Amodins A&B, Proliferin, restrictus, A. variecolor, A. Restrictosin, Variecolin, nidulans, A. flavipes, A. humi- Cordycepin, Flavipin, cola, A. niger, A. velutinus, A. Humicolin, Jawaharene, oryzae Velutinin, Hydroxyaspergillic acid, respectively. Streptomyces thermotolerans Carbomycin A. fumigatus Helvonic acid, Fumigallin, Trypacidin Streptomyces peucetius Daunorubicin Beauveria bassiana Oosporein

For personal use only. Streptomyces argillaceus Mithramycin Cephalosporium cellulens, Sellenin (Cellulenin), C. salmosynnematum Cephalosporins Streptomyces natalensis Pimaricin Cephalosporium sp. Cephalothecin Streptomyces ambophaciens Spiramycin Clavariopsis aquatic Citrinin Streptomyces fradiae Tylosin Dendrodochium toxicum Dendrodochin Streptomyces coelicolor Actinorhodin Fusidium coccineum Fucidin Streptomyces clavuligerus Cephamycin C Paecilomyces persicinus, P. var- Cephalosporin N, Variotin, ioti, P. brefeldianum, P. fre- Brefeldin, Frequentin, Cyanein, quentans, P. cyaneum, P. Canescin, Albidin, canescens, P. albidum, P. nota- Xanthocillin, Nordin, tum, P. paxilli, respectively. Streptomyces maritimus Enterocin Oospora aurantia, O. colorans, O. Oosporein, Virescin, respectively. virescens Streptomyces roseofulvum Frenolicin Cephalosporium sp. Synnematin Streptomyces lincolnensis Lincomycin Fusarium lateritium, Fusarium sp. Locabiotal, Chlamydosporins, respectively. Streptomyces coelicolor Methylenomycin Critical Reviews in Microbiology Downloaded from informahealthcare.com by University of South Carolina on 05/29/15 Streptomyces rimosus Tetracyclin Streptomyces pristinaespiralis Pristinamycin Streptomyces alboniger Puromycin Streptomyces glaucescens Tetracenomycin Streptomyces cattleya Thienamycin Streptomyces sp. Novobiocin Streptomyces sp. P-8648 Viridogrisein Thermophilic actinomycetes Thermomycin, Thermocyridin, Refcin (anthracin)

*Data collected from multiple articles available at http://www.ncbi.nlm.nih.gov/pubmed and http://www.scopus.com/home.url using key words for bacteria and fungal origin antibiotics. DOI: 10.3109/1040841X.2013.875982 Antibiotrophs: The complexity of antibiotic-subsisting 3

resulted in more cases of multi-drug-resistant strains (MDR) gradually adapt and develop mechanisms for voiding anti- (Nakata & Tang, 2008, Sahoo et al., 2010, Magiorakos et al., biotic-induced toxicity, thus progressively improving fitness 2012). Combating MDR with proficient, pragmatic strategies cost. It is now required to deal with antibiotic metabolizers will be necessary to put a halt to the expansion of resistance and panresistant strains – microbes, which have been exposed and to develop adequate therapies. In this review, we assess to all known clinical antibiotics and have demonstrated the underlying factors linking natural microbial antibiotic resistance to every single one of them (Dhar & McKinney, production, multidrug resistance, and antibiotic subsistence. 2007). These bacteria reveal a new cohort of resistant We also present promising approaches to combat nosocomial microorganisms, as they differ from the naturally occurring, pathogens and panresistant strains. primeval antibiotic-resistant microbiota.

Emergence of antibiotrophs Perspectives of antibiotic catabolism and origin of resistance The commonality of antibiotic resistance in microorganisms over the past several decades reveals the frightening tenacious The ethnopharmacolic focus drastically changed in the 20th pliability of microbes, including pathogens. The World Health century as microorganisms with various antibiotic-producing Organization (WHO), the Centers for Disease Control (CDC), capabilities were identified (Goldberg et al., 1999; Rahmati and private groups such as the Infectious Disease Society of et al., 2002). It eventually became apparent that, in nature, America (IDSA) have recognized antibiotic resistance as a actinomyces and bacteria undertake the vast majority of pandemic (Anderson, 1999; Magiorakos et al., 2012; Robicsek, antibiotic synthesis. Currently, over 80% of clinically used 2005). Dantas et al. (2008) isolated microbes that were antibiotics are derived from soil-dwelling bacteria, and the resistant to a plethora of antibiotics and capable of catabolizing benefits have been manifested through their applications in non-synthetic, synthetic, and semi-synthetic antibiotics, surgical transplants, everyday infections treatment, and as including amphenicols, at concentrations 50 times higher chemotherapeutic agents and agrochemicals (Besier et al., than what is considered normal resistance threshold. The 2007; Effmert et al., 2012; Woappi et al., 2013). isolates not only escaped the cytotoxic effects of the peptides, The appearance of antibiotic-resistant microbes within but also were able to catabolize and subsist under them in an health care centers was the first indication of an evolving environment free of alternative carbon source. Recently, microbial resistance. This paved the way for the development numerous strains of Salmonella featuring antibiotic-subsisting of several synthetic and semisynthetic antibiotics, such as abilities were isolated (Barnhill et al., 2010), and chloram- Prontosil (reviewed by Barr, 2011; Foster & Woodruff, 2010). phenicol-subsisting isolates were identified later in Asia (Xin In the 1950s, numerous strains of MDR were identified in et al., 2012). The variety of bacteria adapting to proliferate hospitals and clinics around the world. This was driven by the under harsh environmental conditions, e.g. extreme dosages of exposure of pathogens to sub-inhibitory antibiotic levels, antibiotics lethal to normal microorganisms, could be referred For personal use only. which increased the clinical demand for more potent to as ‘‘antibiotic-resistant extremophiles (AREs)’’ (Gabani antibiotics and abruptly halted the search for natural anti- et al., 2012). Here we propose the term antibiotrophs, from biotics. The research refocus was almost entirely centered on the Greek anti (against), bio (life) and trophe (food), to designing novel synthetic antibiotics, with the hope that their depict microorganisms capable of subsisting in environments chemical compositions would be foreign enough to nature to containing abnormally elevated antibiotic concentrations or prevent bacteria from developing resistance. antibiotics as the sole carbon source. In 1959, a promising synthetic antibiotic, methicillin, was designed and introduced in clinics and hospitals worldwide. Antibiotrophic niches A chronicle of these occurrences was elegantly presented and reviewed (Foster & Woodruff, 2010). Such antibiotics were Microorganisms (i.e. bacteria and fungi) possessing resistance further complemented by the advent of quinolones, but this and catabolic capacities against specific antibiotics and/or bio- approach was again disappointingly interrupted with reported chemicals within unusual microenvironments (Barnhill et al., cases of nalidixic acid-resistant strains, then extremely drug- 2010; Dantas et al., 2008; Frank-Petersise et al., 2011; Gabani resistant strains (XDR) such as vancomycin-resistant enter- et al., 2012; Singh & Walker 2006; Xin et al., 2012) can be Critical Reviews in Microbiology Downloaded from informahealthcare.com by University of South Carolina on 05/29/15 ococci (VRE), penicillin-resistant Streptococcus pneumonia referred to as antibiotrophs. Anthropocentric activities have (PSRP), and eventually totally resistant strains (TDR), notably undoubtedly been the paramount catalysts in the development methicillin-resistant Staphylococcus aureus (MRSA) (Canton of this resistant cohort. Increases in intercontinental travels, & Morosini, 2011; Magiorakos et al., 2012; McAdam et al., farming, and soil exchange within human settings have 2012; Tenover, 2006). Over half a century later, TDR strains exposed these strains – along with the rest of the resistance- remain the leading cause of nosocomial infections in the bearing microbial flora in nature – to human therapeutics world (Maal-Bared et al., 2013), confirming the ineffective- (Baquero et al., 2013; Barbe et al., 2004; Canton & Morosini, ness of synthetic and semisynthetic antibiotics as a long-term 2011; Falagas & Billiziotis, 2007). Through these exposures, solution against antibiotic resistance. antibiotrophs likely developed metabolic enzymes while The overproduction, overuse and misuse of antibiotics retaining their unique catabolic competence (Figure 1). have made it commonplace for microbial populations to be in The absence of alternative nutritional carbon-resources in contact with sub-therapeutic levels of antibiotics in the environments with high human presence is quite rare environment. These sub-inhibitory exposures have allowed and was therefore believed to be a poor driving criterion for strains possessing intrinsic antibiotic resistance traits to the emergence of antibiotic-subsisting bacteria. However, 4 Y. Woappi et al. Crit Rev Microbiol, Early Online: 1–14 Figure 1. Schematic illustrating four central anthropocentric hubs of the antibiotic- subsisting resistance (not to scale). Commensal, industrial, and waste sites pro- vide an abundant nutritional source for antibiotrophs; the latter eventually find their way to human communities via farm manure translocations, hospital visits, and industrial waste dumping.

Table 2. Microbial species possessing antibiotic resistant and subsisting abilities.

Antibiotrophic Microorganisms/family Mechanism of degradation Subsistence characteristics Reference Streptomyces* MDR efflux pump Tetracycline producer Barnhill et al., 2010; D’Costa et al., 2011 Salmonella enterica* Veterinary associations Barnhill et al., 2010 Burkhodelriales N/A Fenitrothion degradation D’Costa et al., 2011 Enterobacteriales Inactivation by beta-lactamases Elevated antibiotic resistance Actinomycetales Ribonucleic acid mutations Elevated antibiotic resistance Rhizobiales N/A Elevated antibiotic resistance Pseudomonadales N/A Elevated antibiotic resistance Zhongli et al., 2001 Sphingobacteriales Inactivation by beta-lactamases Elevated antibiotic resistance Chopra et al., 2003; D’Costa et al., 2011 Sphingosinicella microcystinivorans Microcystin degradation by Elevated antibiotic resistance Chopra et al., 2003 For personal use only. Hydrolysis Citrobacter sp. Erythromycin degradation by Antibiotic Inactivation Foster & Woodruff, 2010 beta-lactamases

*Several orders; N/A: not available

subsistence on antibiotics as a sole carbon source has been et al. (2008) observed higher antibiotrophic activity in urban shown to be the central benchmark of their existence soils compared to soil obtained from farmlands, with most (Maruyama et al., 2006; Nybom et al., 2008; Xin et al., isolates belonging to the Proteobacteria, Antinobacteria and 2012). The antibiotrophic grouping is evidently much larger Bacteroidetes phyla, with Burkholderiales, Pseudomonadales than originally anticipated, and embodies microorganisms and Enterobacteriales representing the most populous orders. capable not only of subsistence, but also of MDR gene Health care centers, clinics, and agricultural environments are transmission, antibiotic detoxification, and even antibiotic locations likely harboring the most elevated populations of production (Barnhill et al., 2010, Xin et al., 2012, Walsh these microbes. Given their resistance, antibiotrophs’ gen- Critical Reviews in Microbiology Downloaded from informahealthcare.com by University of South Carolina on 05/29/15 et al., 2013, Martinez & Rojo, 2011) (Table 2). They omic profile likely possesses an enhanced degree of trans- principally differ from most resistant microbes by their missibility and a widespread pathogenic spectrum (Hawkey & ability to both neutralize and catabolize antibiotics for Jones, 2009; Maal-Bared et al., 2013). nutrition and cellular homeostasis (Barnhill et al., 2010; Martinez, 2006; Romero et al., 2011; Xin et al., 2012). This Mechanisms driving antibiotic resistance in cohort certainly incorporates microorganisms able to subsist antibiotrophs on abnormally elevated antibiotic gradients, whether present as the sole carbon sources or not. The paramount mechanisms underlying the development of In past, studies have revealed the diversified microbio- antibiotic resistance include gene mutations and the acquisi- sphere upsurge in the evolutionary development of new tion of exogenous genetic material, such as plasmids which antibiotic resistant microorganisms (Dhar & McKinney, 2007; contain a variety of resistance genes (Baquero et al., 2013; Gabani et al., 2012; Magiorakos et al., 2012; Singh & Walker, Martinez & Rojo, 2011; Rice, 2012). Most genes involved in 2006). A prominent antibiotrophic niche has been studies antibiotic resistance possess auxiliary functions in bacterial within the veterinary cohort (Barnhill et al., 2010). Dantas species. Many antibiotics naturally produced by microbes DOI: 10.3109/1040841X.2013.875982 Antibiotrophs: The complexity of antibiotic-subsisting 5

have been shown to be involved in microbial survival MDR efflux pumps pathways (e.g. streptomycin) (Martinez & Rojo, 2011; The evolution of MDR efflux pumps in the development of Meroueh et al., 2003). Therefore, it can be assumed that in pathogenic antibiotic resistance has raised concerns (Poole, nature, the function of antibiotics goes beyond inhibiting the 2005). MDR efflux pumps are a common way that microbes growth of the competing microbial flora, and that many genes expel physiological substrates, non-antibiotic substrates, and responsible for antibiotic resistance also have metabolic roles antibiotics outside the cell (Brown et al., 1999; Liang et al., in the survival of the microorganism. In Providencia stuartii, 1995). Five different protein-based efflux pumps have been intrinsic chromosomal acetyltransferases are involved in identified: (i) the multidrug and toxic compound extrusion aminoglycoside resistance, but their primary role, prior to (MATE) (Brown et al., 1999), (ii) the adenosine triphosphate the introduction of aminoglycosides in clinics, was to (ATP) binding cassette (ABC) (Springman et al., 2009), (iii) acetylate peptidoglycan for structural modifications (Barlow the small multidrug resistance (Paulsen et al., 1996), (iv) the & Hall, 2002; Goldberg et al., 1999). Some of the mechan- major facilitator superfamily (Marger & Saier, 1993), and (v) isms underlying the process of antibiotic resistance acquisi- the resistance nodulation cell division (Saier et al., 1994). tion are elaborated below. It has been thought that MDR efflux pumps originally evolved in antibiotic-producing microbes to exocytose the antibiotics Horizontal gene transfer from their cytoplasm as well also evade other naturally produced toxic molecules, thereby allowing the microbe to Horizontal gene transfer (HGT) is the process by which genes survive in its ecological niche (Brown et al., 1999; Rahmati from one species of organism are transferred to another et al., 2002). Helling et al. (2002) reported that the natural species. In bacteria, HGT mostly occurs with genes located on function of efflux pumps in E. coli was to remove metabolic plasmids. Transformation (acquisition of exogenous DNA products and toxins and to buffer the organism against surges often located in the environment), conjugation (acquisition of in pools of potentially toxic metabolites. In addition, there DNA directly from another bacteria), and bacteriophage have been studies confirming the role of efflux pumps in cell- transduction (acquisition of DNA via viral infection) are to-cell signaling, such as quorum sensing (Rahmati et al., major modes of HGT. It has been widely accepted that 2002). The HGT of MDR efflux pumps is now being thought plasmids can harbor a vast variety of antibiotic resistance of as an important mechanism by which many pathogenic genes. Modern biotechnology and refined therapeutics for bacteria have become resistant to a wide range of antibiotics. blocking HGT can allow us to halt the spread of antibiotic It is believed that MDR efflux pumps have auxiliary resistance genes such as R plasmids, which have been known physiological roles including the expelling of toxic endogen- to include genes for resistance to chloramphenicol, tetracyc- ous metabolites as well as exogenous chemicals. The line, aminoglycosides, and sulfonamides as well as other observation that most MDR efflux pumps are chromosomally classes of antibiotics (Hammami et al., 2009; Islam et al., encoded indicates that they did not appear due to the

For personal use only. 2012). The R plasmids, originally found in organisms that widespread use of antibiotics (Nikaido, 2009). This is produced antibiotics, have found ways to naturally transform exemplified by the acrB gene of E. coli, which is used for pathogenic bacteria (Kopmann et al., 2013). protection against bile salts and other detergents abundant in In plasmids, the resistant genes are components of the E. coli microenvironment (i.e. the intestinal tracts of transposons, which are able to insert themselves in the vertebrates) (Zeibell et al., 2007). In P. aeruginosa, which middle of any DNA sequence (Liebert et al., 1999). It has lives mainly in the soil, the MDR efflux pumps are involved been reported that a plasmid-mediated quinolone resistance in pumping toxic compounds produced by other soil micro- gene, qnrA1, was present on a mobile plasmid and was able to organisms (Kang & Gross, 2005). These pumps have also spread to other species of bacteria that were under the been reported to secrete secondary metabolites produced by selective pressure of fluoroquinolones and b-lactam anti- plants, as well as toxic metals such as Co2+,Ni2+,Cd2+, and biotics (Chowdhury et al., 2011). Cantas et al. (2012) Zn2+ (Goldberg et al., 1999). confirmed that in Aeromonas hydrophila, the R-plasmid pRAS1 carrying resistance genes TcR, TmR, and SuRwas Effects of mutations transferred to other species of bacteria by conjugative transfer. Critical Reviews in Microbiology Downloaded from informahealthcare.com by University of South Carolina on 05/29/15 In E. coli, the IncF plasmids, carrying the blaCTX-M-14 gene Overall, antibiotic resistance in bacteria is influenced by the responsible for ceftazidime and defotaxime resistance, are colony’s physiological status. It is believed that the first few known to spread via HGT (Kim et al., 2011). Several other cells that start a colony ultimately determine the final status of plasmid-encoded genes, such as b-lactamases, are known to the colony at the end, as all cells within a colony are clones of have been acquired by pathogenic bacteria via HGT (Meroueh each other. Similarly, if a population of bacteria is exposed to et al., 2003). It has been suggested that the frequency of antibiotics and a few survive, their genome will ultimately conjugative transfer of resistance genes in nature is several determine the characteristics of the future colonies they magnitudes higher than under laboratory conditions (Tenover, generate. In such instances, when a bacterial population is 2006). In addition to conjugative transfer, in Streptococci, exposed to antibiotics, a population is always left behind. Meningococci, and related genera, the exchange of genetic This strategy used by most bacterial populations is now material occurs mainly via transformation (Springman et al., thought to be a way by which bacterial populations generate 2009). In Acinetobacter sp. ADP1, it was shown that the strain strains able to survive extreme changes in their environment was exceptionally capable of acquiring DNA from its (Dhar & McKinney, 2007). This phenomenon, termed the environment (Barbe et al., 2004). founder effect, is thought to give rise to antibiotic-resistant 6 Y. Woappi et al. Crit Rev Microbiol, Early Online: 1–14

populations of bacteria when they are exposed to antibiotics ‘‘Acquired’’ MDR strains, however, are usually derived produced by naturally occurring bacteria. This effect is moieties whose resistant abilities were obtained through different from what is known as persistence, in which cells HGT, this includes a series of pathogenic strains possessing a may survive the first treatment of antibiotics, but are still cutting-edge antibiotic-resistant profile (Thomson & Amyes, sensitive to the antibiotic and will be killed with a second 1992; Wright, 2005). treatment (Kumarasamy et al., 2010). The founder effect, Antibiotrophs are likely the result of perpetual gene on the other hand, has been linked to the ability of microbes interchange, and typical methodologies for antibiotic resist- to go through gain-of-function mutations (hypermutator ance inhibition may prove particularly inefficient against this phenotype) and acquired resistance. subset of resistant microbes. This is made evident by the Many bacterial species possess a special phenotype concept of ‘‘co-resistance’’ as described by Canton et al. termed the hypermutator phenotype, which allows bacteria (2011), and by the realization that certain bacteria not only to quickly adapt by mutating their genomes, allowing them resist antibiotics they are exposed to, but can also derive an to survive in a quickly changing environment. Kenna et al. advantage from that environment (Canton & Morosini, 2011). (2007) reported that P. aeruginosa contained a mutS gene It is expected that future findings will reveal several TDR that allowed it to swiftly adapt to antibiotic treatments in strains as antibiotrophs. cystic fibrosis (CF) patients. In addition to P. aeruginosa, One promising discovery is the identification of peptides isolates of H. influenza and S. aureus from CF patients have with metabolic-hindering properties (Rajgarhia & Strohl, a high proportion of mutators. Small colony variants of 1997). This is unexpectedly the case for tetracycline, whose S. aureus have been isolated from a variety of drug-resistant polyketide origins have revealed anti-catabolic properties chronic infections including CF (Besier et al., 2007). against nearly 600 antibiotic-subsisting isolates (Barnhill A thymidine-dependent SCV isolated from CF patients has et al., 2010). Although one of the earliest antibiotics been shown to be a hypermutator and antibiotic-resistant introduced in clinic, tetracycline was one of the latest (Besier et al., 2008). antibiotics to have a clinical case of resistance reported The majority of naturally occurring mutants have defects in against it. In contrast, recent findings analyzing the evolution the methyl-directed mismatch repair (MMS) system proteins of antibiotic resistance have demonstrated drastically (Oliver et al., 2004). Several other genes encoding beta-clamp increased rates of vancomycin, nalidixic acid, and strepto- proteins, mutH, mutL, and mutU, have also been studied mycin resistance (Arias & Murray, 2012; Robicsek et al., (Chopra et al., 2003). In Bacillus anthracis, the knockouts of 2005). An inventory of antibiotics commonly metabolized mutY and mutM combination resulted in high mutation rates, and subsisted on by antibiotrophic strains is summarized but mutY and mutM single knockouts were weak mutants in Table 3. (Zeibell et al., 2007). In addition to mut genes, the DNA Secondary metabolites’ influence on exaptation also plays adenine methyltransferase (Dam) genes play a role in repair a central role in the localization of microbial niches, as the

For personal use only. mechanisms (Nikaido, 2009). Organisms lacking Dam are effects of cell-to-cell signaling through quorum sensing can hypersensitive to DNA-damaging agents and reactive oxygen enable natural microbial dispersions (Martinez, 2006). Within species (Zaleski and Piekarowicz 2004), while organisms with the microbiosphere, antibiotics can serve as warning signs, this hypermutator phenotype can acquire antibiotic resistance and can induce biofilm formations in neighboring microbial if faced with stresses such as high antibiotic levels. populations (Tsui et al., 2011). Such metabolites can also serve as chemoattractants that appeal to certain antibiotrophs, concomitantly selecting strains needed in specific micro- Risks of an antibiotic-subsisting resistance environmental milieus (Romero et al., 2011; Woappi et al., The unsettling concept of antibiotic subsistence subsequent to 2013; Zhang et al., 2011). Hence, human commensals, health/ antibiotic resistance has been examined by several groups research centers and agricultural/farm soils, again, are (Barnhill et al., 2010; Lee et al., 2008; Walsh et al., 2013; attractive niches for these microorganisms, as they can readily Xin et al., 2012). As explained above, the acquisition of gain access to the elevated antibiotic concentrations common resistance is a natural phenomenon that can serve to maintain in those environments. balance within the microbiome. The problem, however, Critical Reviews in Microbiology Downloaded from informahealthcare.com by University of South Carolina on 05/29/15 presents itself when the resistance is acquired by strains Catabolic conduits whose pathogenicity affects humans or animals and crops closely associated with humans. Furthermore, contemporary A microbe’s ability to catabolize extreme antibiotic levels classifications fail to properly categorize resistant strains, and requires its genomic adaptation to stretch beyond the mere often encompass ‘‘intrinsic’’ MDR strains and ‘‘acquired’’ procurement of MDR pumps. Their potential swarming MDR strains alike, even though a strong genomic distinction motility and chemoattractant patterns are revealed by their distinguishes the two (Magiorakos et al., 2012). This leads to appeal toward elevated antibiotic gradients in microfluidic a distorted theoretical approach, since hypermutator charac- devices, which also provide insights about their probable teristics often alter therapeutic targets (Chopra et al., 2003, pathogenic mode of action (MOA) (Hawkey & Jones, 2009; Lee et al., 2008). We must be aware that ‘‘intrinsic’’ MDR Martinez & Rojo, 2011; Zhang et al., 2011). In actuality, strains are principally resistant gene propagators within the antibiotrophs may necessitate ‘‘intake pumps’’ – modified microbiome (i.e. the totality of microbes), as they generally efflux pumps driven by mechanisms analogous to the represent antibiotic-resistant populations present prior the phosphotransferase system (PTS), but used to ingest extra- introduction of antimicrobials in clinics (Allen et al., 2010). cellular antibiotics – while possessing expulsive efflux pumps DOI: 10.3109/1040841X.2013.875982 Antibiotrophs: The complexity of antibiotic-subsisting 7

Table 3. Antibiotic inventory frequently subsisted on by antibiotrophs.

Most-often degraded (High MIC) Reference Often degraded (Low MIC) Reference Erythromycin (120 mg/ml) Frank-Petersise et al., 2011 Rifampin (40 mg/l) Foster & Woodruff, 2010; Singh & Walker, 2006 Ampicilin (41 mg/ml) Barnhill et al., 2010 Tetracylcline (51 mg/ml) Barnhill et al., 2010 Clavulanic acid (41 mg/ml) Cefepime (51 mg/ml) Sulfisoxazole (41 mg/ml) Florfenicol (51 mg/ml) Trimethoprimb (41 g/ml) Amikacin (51 mg/ml) Kanamycin (1 g/l) Dantas et al., 2008; Barnhill et al., 2010 Ceftiofur (51 mg/ml) Vancomycin (1 g/l) Levofloxacin (1 g/l) Aminov & Mackie, 2007 Penicillin G (1 g/l) Dantas et al., 2008 Sulfisoxazole (1 g/l) Ciprofloxacinb (1 g/l) Sulfamethizole (1 g/l) Mafenide (1 g/l) Clindamycin (20 mg/ml) Trimethoprim (1 g/l) Novobiocin (20 mg/ml) Chowdhury et al., 2011 Carbenicillin (1 g/l) Chloramphenicol (1 g/l) Sisomicin (1 g/l) Amikacin (1 g/l) Daptomycin (1 g/l) Chowdhury et al., 2011 Rifampicin (1 g/l) Trimethoprimb (51mg/ml) Vancomycin (51mg/ml)

b ¼ cited both as highly degraded and as least degraded; NA ¼ Not Available.

Figure 2. Hypothetical antibiotic-metaboliz- ing pathway of ciprofloxacin, a second- generation fluoroquinolone frequently degraded by antibiotrophs. Subsistence on antibiotics is enabled by phosphatases and hydrolases capable of efficient antibiotic deactivation and degradation inter and intra- cellularly; degraded antibiotics are consumed as carbon source and excess contents are expelled via MDR efflux pumps. For personal use only. Critical Reviews in Microbiology Downloaded from informahealthcare.com by University of South Carolina on 05/29/15

only for antibiotics they cannot metabolize, or for concentra- should be investigated (Martinez & Rojo, 2011; Qu & Spain, tions surpassing their intake threshold (Figure 2). For this 2011). reason, proton motive force protein such as secF, seen in the potentially prominent antibiotroph order Burkholderiales,in Antibiotic production versus antibiotrophism concert with antibiotic-metabolizing genes may be red flags for antibiotrophism (Chopra et al., 2003; Hawkey & Jones, The origins of microbial antibiotic production stemmed from 2009). Furthermore, molecular and genomic elements the diversification of prehistoric biomes. Antibiotic resistance involved in the regulation of carbon and nitrogen utilization arose afterwards as a self-protective mechanism against 8 Y. Woappi et al. Crit Rev Microbiol, Early Online: 1–14

microbes’ own metabolites, and as a superficial protective enabled microbiologists to tag commonly recognized gene mechanism against extraneous environmental toxins (Davies clusters as probable antibiotic-catabolizing elements & Davies, 2010; Tenover, 2006; Wright, 2005). The presence (Barnhill et al., 2010; Kopmann et al., 2013; Tsui et al., of resistant genes was mostly trivial in antibiotic-producing 2011). Another example is L-tryptophan, whose degradation microbes. Over time, however, the antibiotic resistance in antibiotic-producing microbes unleashes its indole func- genome has acquired elements that often enable it to confer tional group and subsequently confers antibiotic resistance virulence (Baquero et al., 2013; Martinez, 2012). It has been (Lee & Collins, 2012). Such mechanisms reinforce the found that MDR efflux pumps, for instance, originated in pleiotropic characteristics of subsistence and indicate a microbes that produced antibiotics and parvomes (Allen et al., potential presence of auxiliary antibiotic-subsisting genes 2010; Dhar & McKinney, 2007). Streptomyces rimosus,a camouflaged within ordinary antibiotic-resistant clusters tetracycline producer, possesses MDR efflux pumps, which it (Canton & Ruiz-Garbajosam, 2011). uses to expel antibiotics (Petkovic et al., 2006). More recently, Furthermore, comparative proteomic (i.e. global study of the coexistence of antibiotic production and resistance proteins) analysis could help reveal the MOA of several functions has been confirmed by studying the gene nexus antibiotrophic strains. The application of PM47 treatment, as within antibiotic-producing cassettes (D’Costa et al., 2011; demonstrated by Wenzel & Bandow (2011), has shown Islam et al., 2012; Nikaido, 2009). This presents a pertinent distinctive proteomics markers underlining antibiotic-resistant concern, as it reveals some of the antibiotic-producing MOA in several species. Another comparative proteomic microbiota to be part of the antibiotrophic strains, with study reveals bacteria resistant to different antibiotic drugs virulence transmissibility and pathogenicity competence with distinct mechanisms of action, along with an overview of (Gabani et al., 2012; Gillings, 2013; Palmer & Keller, 2010; the proteins possibly related to the resistance process (Lima Singh & Walker, 2006; Torres-Cortes et al., 2011). et al., 2013). Analogous gene-specific approaches would The implications of antibiotic production and antibiotic provide an extremely dynamic scaffold for antibiotrophic subsistence raise some interesting questions. Could certain genomic mining, which could enable us to determine whether antibiotrophic strains be self-sufficient under stressful condi- genes, in synergy with antibiotic-inducing elements such as tions by producing antibiotics they can also digest? Are S12 ribosomal proteins, are concrete indicators of subsist- antibiotrophs catabolically restricted to exogenous metabol- ence. These uncharacteristic arrangements can readily be ites? Genomic mining and metabolic mapping can provide an assessed through pyrosequencing if performed with primers enormous amount of information relevant to such queries. hypersensitive to subsisting genes (Table 4). Furthermore, traditional molecular cloning approaches Proteogenomic expression profiles are increasingly through the insertion of specific resistant cassettes upstream important in the search for functional biomolecules (i.e. from a macrolide promoter may provide a swift method of metabolites) that may have potential uses in eliminating determining minimal genomic requirements and mechanisms antibiotic resistance. The vast amount of data produced from

For personal use only. underpinning antibiotic production, molecule transportation, genome and proteome data sets needs to be analyzed, and one and subsistence acquisition in several resistant strains must understand the analytical platforms that have been used (Bergstrom et al., 2004; Chowdhury et al., 2011; to obtain the data and the statistical principles. The current Kumarasamy et al., 2010; Torres-Cortes et al., 2011). infrastructure of bioinformatics allows the generation, storing, Therefore, in addition to catabolic patterns, the use of analysis, and interpretation of these data sets. In general, data molecular determinants is necessary to accurately describe interpretations of antimicrobial drugs in terms of genomics subsistence in bacteria. Studies analyzing catabolic behaviors and proteomics have been rendered through three major in resistant strains, for instance, have shed light on the scarcity bioinformatics approaches: (i) mathematical modeling (i.e. of truly, solely, antibiotic-subsisting bacteria (Walsh et al., data mining, statistical analysis, genetic algorithms, and graph 2013), emphasizing the need for genomic and systems biology matching); (ii) computation search alignment techniques (i.e. in characterizing subsistence. comparing new proteomes and metabolomes against the set of known proteins and metabolites); and (iii) a combination of critical mathematical modeling and search techniques. Bioinformatics of antibiotic resistance Among the search tools, there are a number of databases Critical Reviews in Microbiology Downloaded from informahealthcare.com by University of South Carolina on 05/29/15 Global in silico approaches, precise transcriptomics (i.e. of antibiotic peptides treating microbial infections global study of mRNA/transcripts) and advanced metage- (e.g. ANTIMIC, PhytAMP, APD2 and CAMP) that provide nomic systems (i.e. global gene profiles of uncultivable an overview of antibiotic resistance (Brahmachary et al., bacteria) can now enable us to identify members of the 2004; Chowdhury et al., 2011; Thomas et al., 2010; antibiotroph subset based on specific molecular profiles. Wang et al., 2009). Consequently, instead of looking for the mere ability to The antibiotic resistance gene database (ARDB) unifies subsist in carbon-free environments under elevated antibiotic most of the publicly available information on antibiotic concentrations, we can mark specific genomic elements as resistance (Liu & Pop, 2009). The antimicrobial drug strong indicators of antibiotrophism. By doing so, it is database (AMDD) provides a comprehensive platform with possible to establish solid foresight strategies and to accur- the potential to help analyze antimicrobial agents and develop ately anticipate possible expansions and transmutations within new candidates to overcome drug resistance (Danishuddin the microbial resistome (i.e. antibiotic resistance genes). et al., 2012). Developments in the Internet have allowed The identification of the SG11 integron and secF gene researchers to have immediate access to information in almost in several antibiotic-subsisting isolates, for instance, has every scientific field. Table 5 summarizes a list of Internet DOI: 10.3109/1040841X.2013.875982 Antibiotrophs: The complexity of antibiotic-subsisting 9

Table 4. Prospective molecular elements conferring subsistence.

Molecular agent(s) Host Mode of action (MOA) Reference SGI1 integron Salmonella enterica Genomic island carrying resistance Barnhill et al., 2010 gene cassettes Sul1 Salmonella (*) Gene conferring sulfonamide resistance L-tryptophan S. aureus Degradation-dependent indole aids Lee & Collins, 2012 efflux pump functioning L-arginine Streptococcus sp., Escherichia coli, Ferton reaction suppression and Zhao-Lai et al., 2012; Klebsiella sp catalase activation Lee & Collins, 2012 CTX-Ms Enterobacteriaceae b-lactamase-driven hydrolysis Thomson & Amyes, 1992 2NI nitrohydrolase Nocardia mesenterica, Pseudomonas Hydrolytic denitration Qu & Spain, 2011 Fluorescens, Streptomyces eurocidicus secF Burkholderiales Protein translocation through Barnhill, 2010; Kazuya et al., 2011 proton motive force MlrA Sphingomonas/Sphingomonadaceae Hydrolysis. MCLR transport Kormas & Lymperopoulou, 2013; MlrB Borgia et al., 2012 MlrC MlrD NDM-1 Enterobacteriaceae Carbapene degradation Borgia et al., 2012 CbrA Pseudomonas aeruginosa Sensor kinase driving metabolic Jin et al., 2002 switching in swarmer cells OPH Pseudomonas sp. Organophosphate degradation Singh & Walker, 2006 pehA Burkholderia caryophilli Gene responsible for polygalactur- onase expression glp A&B Pseudomonas sp. Invovlved in commensalism adaptations tet(S) Staphylococcus aureus, Bacillus sp. Gene driving tetracycline-efflux Falagas & Bliziotis, 2007; transporter expression and Lee & Collins, 2012 catalysis of Na+ and K+ mphA E. coli Macrolide inactivation Wright, 2005 mphB E. coli mphBM S. aureus

*Several orders.

resources that may be useful to practitioners and scientists Recently identified antibacterial reagents capable of evicting

For personal use only. with research interests in antimicrobial resistance (adopted antibiotic-resistant plasmids from a cell, such as apramycin, and modified from (Falagas & Karveli, 2006). may prove particularly appealing for this approach (Denap et al., 2004). In addition, it has been recognized that the mass production of antibiotics has generated an array of logistic Challenges and future perspectives challenges that have resulted in their overuse and misuse. As Our dependence on antibiotics for agriculture and disease noted by the CDC, the unmonitored dumping and distribution treatment is higher today than it has ever been. Nonetheless, of ineffective antibiotics in developing nations provides an we concurrently face the challenge of an unprecedented, enormous nutritional bank for antibiotic-resistant microbes, evolving microbial resistance. Unlike most microorganisms and is a major driving factor for the expansion of the pan- and pests, our story is intertwined with that of bacteria. resistant resistome (Okeke et al., 1999). Although inconveni- The symbiotic relationship that exists between humans and ent, an approach averse to modern antibiotics will need to be microbes will prevent us from eradicating several microbial introduced within the next decade. Ingenuity and foresight strains, even if hypothetically feasible. Not by virtue of should be encouraged in the planning of the next therapeutic coincidence, human commensal is a frequent recipient models. The use of bacterial repellents, for instance (i.e. Critical Reviews in Microbiology Downloaded from informahealthcare.com by University of South Carolina on 05/29/15 of pathogenic traits (Marshall & Ochieng, 2009). This is biotoxic and microtoxic inhibitors), may be a better thera- seen in ESBL-producing E. coli, a pivotal mediator of peutic strategy than the current bactericidal approach. Such resistant gene interchange between environmental micro- cytotoxin neutralizers can prove particularly effective since organisms, commensals, and nosocomial pathogens (Kurihara they do not threaten colony viability and hence do not activate et al., 2013; Sengupta et al., 2013). The combination of HGT resistance-favorable mutations, ultimately decreasing the and gene mutations allows such microbes to quickly generate propagation of resistant genes (Baquero et al., 2013; advantageous variances and to produce strains with swift Williams & Hergenrother, 2008; Williams et al., 2011). antibiotic resistance propensities. Multiple microbial metabolic mechanisms for drug toler- Although a general consensus on the description of ance reveal an ongoing evolution towards extremophiles, antibiotic-subsisting microorganisms is provided in this tolerating environments that are otherwise lethal to a normally review, it is important to halt bacterial evolution and develop occurring bacterium in nature. The limited research on a next generation of antibiotics that would quickly eliminate naturally occurring extremophiles has not allowed us to resistant strains, while subsequently voiding their genomic fully understand the particularities of their niches. However, content to prevent its acquisition by nearby microbes. in-depth studies of antibiotic-resistant organisms that fall into Critical Reviews in Microbiology Downloaded from informahealthcare.com by University of South Carolina on 05/29/15 For personal use only. 10 Table 5. Major International networks and updated world wide websites presenting data on antimicrobial resistance*. .Wap tal. et Woappi Y. Title World Wide Web address** Objectives Source# Antimicrobial Drug http://www.amddatabase.info. A comprehensive database, anti microbial drug database Danishuddin et al., 2012 Database (AMDD), of known synthetic antibacterial and antifungal compounds extracted from the available literature and other chemical databases, e.g. PubChem, PubChem BioAssay and ZINC, etc Antibiotic Resistance http://ardb.cbcb.umd.edu/ Unified publically available information on antibiotic Liu & Pop, 2009 Genes Database resistance. Antimicrobial http://apps.who.int/medicinedocs/en/d/Jh1461e/3.6.html Central Web page for the Antimicrobial Resistance WHO Resistance Information Information Bank Bank Antimicrobial resistance http://www.hpa.org.uk/web/HPAweb&Page&HPAwebAutoListName/ Only resistance data from published documents HPA data Page/1221117908959 included; the Web site focuses on a limited number of bacterial species and antimicrobial agents Drug resistance http://www.who.int/drugresistance/en/ Information on malaria, tuberculosis, and HIV/AIDS WHO The European http://www.ecdc.europa.eu/en/activities/surveillance/EARS-Net/ Information on Escherichia coli, Enterococcus faecalis, EARSS Antimicrobial Pages/index.aspx Enterococcus faecium, Klebsiella pneumoniae, Resistance Pseudomonas aeruginosa, Staphylococcus aureus, Surveillance System and Streptococcus pneumonia Meropenem Yearly http://www.ncbi.nlm.nih.gov/pubmed/10595570 Interactive database providing resistance data and Turner et al., 1999 Susceptibility Test statistics on several bacteria regarding several anti- Information microbial agents since 1997 Collection database Infectious Disease http://www.cdc.gov/ncezid/dpei/ Available infectious disease surveillance data and CDC Surveillance: reports provided by the name of surveillance system, Surveillance by the common disease name, and by the disease Resources Links topic Infectious Disease http://www.cdc.gov/ncezid/ Emerging infections programs in the United States CDC Surveillance: Emerging Infections Programs Antimicrobial Resistance in http://www.cdc.gov/hai/ Data on drug-resistant organisms, prevention and con- CDC Health Care Settings trol, campaigns, and laboratory practices NARMS (National http://www.cdc.gov/narms/index.html NARMS highlights and annual reports CDC for NARMS Antimicrobial Resistance Monitoring System): Enteric Bacteria NARMS http://www.fda.gov/AnimalVeterinary/SafetyHealth/ NARMS data, methods, and publications FDA for NARMS AntimicrobialResistance/ NationalAntimicrobialResistanceMonitoringSystem/ 1–14 Online: Early Microbiol, Rev Crit ucm059103.htm Project ICARE (Intensive http://www.sph.emory.edu/ICARE/publications.php Published data on antimicrobial resistance in the RSPH Care Antimicrobial healthcare system generated from Project ICARE Resistance Epidemiology) publications European Network for http://www.uia.be/s/or/en/1100056543 Peer-reviewed publications about resistance by ENARE Union of International Antimicrobial members since 2003 Associations Resistance and Epidemiology Critical Reviews in Microbiology Downloaded from informahealthcare.com by University of South Carolina on 05/29/15 For personal use only. O:10.3109/1040841X.2013.875982 DOI:

Network on Antibiotic http://www.narsa.net/ Web site on S. aureus NIH and NIAID Resistance in Staphylococcus aureus Reservoirs Of Antibiotic http://www.roarproject.org/ ROAR publications available; registration required for APUA Resistance database access European Surveillance of http://app.esac.ua.ac.be/public/ Interesting interactive database on antibiotic use in DG/SANCO Antibiotic Consumption European countries, among other things European Surveillance of http://www.esbic.de/esbic/ind_esar.htm Overall results of resistance tests; has not been updated ESCMID Antimicrobial since 1999 Resistance Hospital in Europe, Link for http://helics.univ-lyon1.fr/helicshome.htm Online final reports on resistance in intensive care unit IPSE Infection Control settings and for surgical site infections through Surveillance Annual Report of the http://www.paho.org/english/ad/dpc/cd/amr-lima-2004.htm Annual report for 2003, as well as links to Web sites on PAHO, WHO Monitoring/Surveillance prevention and control of communicable diseases Network for Resistance to Antibiotics 2003 Resistance Surveillance http://www.bsacsurv.org/ Data on antimicrobial resistance for respiratory tract BSAC Website infections and bacteremia ProMED-mail http://www.promedmail.org/?pp2400:1000 The global electronic reporting system for outbreaks of ISID emerging infectious diseases and toxins; open to all sources Antibiotic/antimicrobial http://www.cdc.gov/drugresistance/index.html Extensive list of links on antimicrobial resistance from CDC resistance–related links US and international sources National/international net- http://www.ecdc.europa.eu/en/activities/ Provides links to national and international RIVM works on antimicrobial surveillance/EARS-Net/Pages/index.aspx networks Web pages on antibiotic resistance. Resistance Antibiotic resistance http://www.antibioresistance.be/Links.html Provides links to Web pages on antibiotic resistance; at Belgian Service of Biosafety and archives the time of our search, some were Inaccessible Biotechnology niitoh:Tecmlxt fantibiotic-subsisting of complexity The Antibiotrophs: Antimicrobial resistance http://www.hpa.org.uk/infections/topics_az/ Data on related topics and links HPA antimicrobial_resistance/menu.htm SSAC links http://www.srga.org/SSAC/links/links.html Links to Scandinavian organizations and other inter- SSAC national organizations that study the antimicrobial resistance. Communicable diseases http://www.health.gov.au/internet/main/Publishing.nsf Links to the Web sites of Australian and international Australian government, surveillance–related organizations and associations studying antimicro- Department of Health and Links bial resistance Aging Antibiotic resistance http://www.antibiotic.ru/en/ar/links.shtml Links to Web pages on antibiotic resistance; at the time Institute of Antimicrobial resources of our search, some of these were inaccessible Chemotherapy and Department of Clinical Pharmacology, Smolensk State Medical Academy

*Adopted (with permission) and modified from Falagas and Karveli (2006). **Last visited Feb. 2013. The searches are performed on PubMed using keywords: resistance, antimicrobial resistance, surveillance network, program and projects etc. The explored webpages are selected from a very extensive catalogue on the basis of the following criteria: they provided international surveillance data, they provided comprehensive and evidence based information and it was easy to access that information. We tried to review most of the major international networks, it is however inevitable that few are overlooked. #WHO: World Health Organization; HPA: Health Protection Agency; EARSS: European Antimicrobial Resistance Surveillance Network; CDC: Center for Disease Control and Prevention; NARMS: National Antimicrobial Resistance Monitoring System; APUA: Alliance for the Prudent Use of Antibiotics; DG/SANCO: Director General for Health and Consumer Affairs; ESCMID: European Society of Clinical Microbiology and Infectious Diseases; IPSE: Improving Patient Safety in Europe; PAHO: Pan American Health Organization; BSAC: The British Society for Antimicrobial Chemotherapy; ISID: International Society for Infectious Diseases; HPA: Health Protection Agency. 11 12 Y. Woappi et al. Crit Rev Microbiol, Early Online: 1–14

the extremophile category (i.e. antibiotrophs) would help us versatile and naturally transformation competent bacterium. Nucl locate thriving properties of many other extremophiles and Acids Res 32:5766–79. Barr J. (2011). A short history of dapsone, or an alternative model of resistant bacterial strains. In addition, it would be advanta- drug development. J Hist Med Allied Sci 66:425–67. geous for future studies to be consistent with terminologies Barlow M, Hall BG. (2002). Phylogenetic analysis shows that the OXA such as subsistence, antibiotic-catabolism, antibiotrophism, beta-lactamase genes have been on plasmids for millions of years. and sole-carbon source utilization. This will aid facilitate the J Mol Evol 55:314–21. Barnhill AE, Weeks KE, Xiong N, et al. (2010). Identification of analytical correlation between various subsisting gene acqui- multiresistant Salmonella isolates capable of subsisting on antibiotics. sition patterns, and will improve surveillance culture Appl Environ Microbiol 76: 2678–80. screening. Bergstrom CT, Lo M, Lipsitch M. (2004). Ecological theory suggests To fully understand the spectrum of this subsistance-based that antimicrobial cycling will not reduce antimicrobial resistance in hospitals. Proc Nat Acad Sci USA 101:13285–90. resistance, the focus should also be orientated towards Besier S, Smaczny C, von Mallinckrodt C, et al. (2007). Prevalence nosocomial environments. The novel antibiotic arsenals and and clinical significance of Staphylococcus aureus small-col- well-known antibiotics associated with resistant strains could ony variants in cystic fibrosis lung disease. J Clin Microbiol 45: be administered solely through compact portable drug pumps 168–72. Besier S, Zander J, Kahl BC, et al. (2008). The thymidine-dependent (PDP) attached to patients. Studies have suggested, ‘‘anti- small-colony-variant phenotype is associated with hypermutability biotic cycling,’’ which involves the periodic replacement of and antibiotic resistance in clinical Staphylococcus aureus isolates. antibiotics with alternative classes of compounds in an Antimicrob Agents Chemother 52:2183–9. attempt to reduce the selection pressure for resistance Borgia S, Lastovetska O, Richardson D, et al. (2012). Outbreak of carbapenem-resistant Enterobacteriaceae containing blaNDM-1, (Masterton, 2005). However, this does not provide a Ontario, Canada. Clin Inf Dis 55:e109–17. long-term solution, since the complete eradication of multi- Brahmachary M, Krishnan SP, Koh JL, et al. (2004). ANTIMIC: a drug-resistant strains is practically impossible. An equally database of antimicrobial sequences. Nucl Acids Res 32:D586–9. promising and currently used approach is the combinations Brown MH, Paulsen IT, Skurray RA. (1999). The multidrug efflux protein NorM is a prototype of a new family of transporters. of various antibiotics with different modes of action. Mol Microbiol 31:394–5. One demonstration of this strategy resulted in great success Cantas L, Midtlyng PJ, Sorum H. (2012). Impact of antibiotic treatments with clavulanic acid and related compounds in combination on the expression of the R plasmid tra genes and on the host innate with b-lactam antibiotics (Jariyawat et al., 1999). However, immune activity during pRAS1 bearing Aeromonas hydrophila infection in zebrafish (Danio rerio). BMC Microbiol 12:37. microbial strains resistant to this mechanism have been found, Canton R, Morosini MI. (2011). Emergence and spread of antibiotic and recent studies have reported clavulanic acid as one of the resistance following exposure to antibiotics. FEMS Microbiol Rev 35: most readily catabolized antibiotics when screened against 977–91. antibiotrophic strains (Barnhill et al., 2010). Canton R, Ruiz-Garbajosam P. (2011). Co-resistance: an opportunity for the bacteria and resistance genes. Curr Opin Pharmacol 11:477–85. As microbiosphere ‘‘cleaning machines’’, the unique Chopra I, O’Neill AJ, Miller K. (2003). The role of mutators in the metabolism observed in antibiotrophs also has some valuable emergence of antibiotic-resistant bacteria. Drug Resist Updat 6: 137–45. For personal use only. and practical potential. Through gene manipulation, non- pathogenic antibiotrophs can be engineered for pharmaceut- Chowdhury G, Pazhani GP, Nair GB, et al. (2011). Transferable plasmid- mediated quinolone resistance in association with extended-spectrum ical, agricultural, and clinical uses. Their chemoattractant beta-lactamases and fluoroquinolone-acetylating aminoglycoside-6’- patterns could be employed to identify hotspots of antibiotic N-acetyltransferase in clinical isolates of Vibrio fluvialis. Int J outflow, while their genomic profiles could help hone Antimicrob Agents 38:169–73. CRISPR interference and could serve as substrates for the D’Costa VM, King CE, Kalan L, et al. (2011). Antibiotic resistance is ancient. Nature 477:457–61. next generation of molecular cloning applications. Danishuddin M, Kaushal L, Hassan Baig M, Khan AU. (2012). AMDD: antimicrobial drug database. Genomics Proteomics. Bioinformatics Acknowledgements 10:360–3. Dantas G, Sommer MO, Oluwasegun RD, Church GM. (2008). Bacteria The authors thank Institutional assistance for making this subsisting on antibiotics. Science 320:100–3. research possible. Davies J, Davies D. (2010). Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev 74:417–33. Denap JC, Thomas JR, Musk DJ, Hergenrother PJ. (2004). Combating Declaration of interest drug-resistant bacteria: small molecule mimics of plasmid incompati-

Critical Reviews in Microbiology Downloaded from informahealthcare.com by University of South Carolina on 05/29/15 bility as antiplasmid compounds. J Am Chem Soc 126:15402–4. The authors report no conflicts of interest. Dhar N, McKinney JD. (2007). Microbial phenotypic heterogeneity and antibiotic tolerance. Curr Opin Microbiol 10:30–8. References Effmert U, Kalderas J, Warnke R, Piechulla B. (2012). Volatile mediated interactions between bacteria and fungi in the soil. J Chem Ecol 38: Allen HK, Donato J, Wang HH, et al. (2010). Call of the wild: antibiotic 665–703. resistance genes in natural environments. Nat Rev Microbiol 8:251–9. Falagas ME, Bliziotis IA. (2007). Pandrug-resistant Gram-negative Aminov RI, Mackie RI. (2007). Evolution and ecology of antibiotic bacteria: the dawn of the post-antibiotic era? Int J Antimicrob Agents resistance genes. FEMS Microbiol Lett 271:147–61. 29:630–6. Anderson RM. (1999). The pandemic of antibiotic resistance. Nat Med 5: Falagas ME, Karveli EA. (2006). World Wide Web resources on 147–9. antimicrobial resistance. Clin Infect Dis 43:630–3. Arias CA, Murray BE. (2012). The rise of the Enterococcus: beyond Foster JW, Woodruff HB. (2010). Antibiotic substances produced by vancomycin resistance. Nat Rev Microbiol 10:266–78. bacteria. Ann NY Acad Sci 1213:125–36. Baquero F, Tedim AP, Coque TM. (2013). Antibiotic resistance shaping Frank-Petersise N, Peekate L, Oriakpono O. (2011). Degradation multi-level population biology of bacteria. Front Microbiol 4:15. doi: of antibiotics by bacteria and fungi from the aquatic environment. 10.3389/fmicb.2013.00015. J Toxicol Environ Health Sci 3:275–85. Barbe V, Vallenet D, Fonknechten N, et al. (2004). Unique features Gabani P, Prakash D, Singh OV. (2012). Emergence of antibiotic- revealed by the genome sequence of Acinetobacter sp. ADP1, a resistant extremophiles (AREs). Extremophiles 16:697–713. DOI: 10.3109/1040841X.2013.875982 Antibiotrophs: The complexity of antibiotic-subsisting 13

Gillings MR. (2013). Evolutionary consequences of antibiotic use for the Marger MD, Saier Jr MH. (1993). A major superfamily of transmem- resistome, mobilome and microbial pangenome. Front Microbiol 4:4. brane facilitators that catalyse uniport, symport and antiport. Trends doi: 10.3389/fmicb.2013.00004. Biochem Sci 18:13–20. Goldberg M, Pribyl T, Juhnke S, Nies DH. (1999). Energetics and Marshall MB, Ochieng DJ. (2009). Commensals: Underappreciated topology of CzcA, a cation/proton antiporter of the resistance- reservoir of Antibiotic Resistance. Microbe 4:231–8. nodulation-cell division protein family. J Biol Chem 274:26065–70. Martin JF, Casqueiro J, Liras P. (2005). Secretion systems for secondary Hammami R, Ben Hamida J, Vergoten G, Fliss I. (2009). PhytAMP: a metabolites: how producer cells send out messages of intercellular database dedicated to antimicrobial plant peptides. Nucl Acid Res 37: communication. Curr Opin Microbiol 8:282–93. D963–8. Martinez JL. (2006). Antibiotics as intermicrobial signaling agents Hawkey PM, Jones AM. (2009). The changing epidemiology of instead of weapons. Proc Natl Acad Sci USA 103:19484–9. resistance. J Antimicrob Chemo 64:i3–10. Martinez JL. (2012). Natural antibiotic resistance and contamination by Helling RB, Janes BK, Kimball H, et al. (2002). Toxic waste disposal in antibiotic resistance determinants: The two ages in the evolution of Escherichia coli. J Bacteriol 184:3699–703. resistance to antimicrobials. Front Microbiol 3:1, doi: 10.3389/ Islam MR, Jeong YT, Lee YS, Song CH. (2012). Isolation and fmicb.2012.00001. identification of antifungal compounds from Bacillus subtilis C9 Martinez JL, Rojo F. (2011). Metabolic regulation of antibiotic inhibiting the growth of plant pathogenic fungi. Mycobiol 40:59–66. resistance. FEMS Immun Med Microbiol 35:768–89. Jariyawat S, Sekine T, Takeda M, et al. (1999). The interaction and Maruyama T, Park HD, Ozawa K, et al. (2006). Sphingosinicella transport of beta-lactam antibiotics with the cloned rat renal organic microcystinivorans gen. nov., sp. nov., a microcystin-degrading anion transporter 1. J Pharmacol Exp Ther 290:672–7. bacterium. Int J Sys Evol Microbiol 56:85–9. Jin J, Guffanti AA, Bechhofer DH, Krulwich TA. (2002). Tet(L) and Masterton RG. (2005). Antibiotic cycling: More than it might seem? tet(K) tetracycline-divalent metal/H+ antiporters: characterization of J Antimicrob Chemother 55:1–5. multiple catalytic modes and a mutagenesis approach to differences. McAdam PR, Templeton KE, Edwards GF, et al. (2012). Molecular J Bacteriol 184:4722–32. tracing of the emergence, adaptation, and transmission of hospital- Kajander EO, Ciftcioglu N. (1999). Nanobacteria as extremophiles. Proc associated methicillin-resistant Staphylococcus aureus. Proc Natl SPIE Int Soc Opt Eng 3755:106–12. Acad Sci USA 109:9107–12. Kang H, Gross DC. (2005). Characterization of a resistance-nodulation- Meroueh SO, Minasov G, Lee W, et al. (2003). Structural aspects for cell division transporter system associated with the syr-syp genomic evolution of beta-lactamases from penicillin-binding proteins. J Am island of Pseudomonas syringae pv. syringae. Appl Environ Microbiol Chem Soc 125:9612–18. 71:5056–65. Nakata M, Tang W. (2008). Japan-China joint medical workshop on Kazuya S, Hideaki M, Kunihiro O, Norio S. (2011). How microcystin- drug discoveries and therapeutics 2008: The need of Asian pharma- degrading bacteria express microcystin degradation activity. Lakes ceutical researchers’ cooperation. Drug Discov Therap 2:262–3. Reserv 16:169–78. Nikaido H. (2009). Multidrug resistance in bacteria. Ann Rev Biochem Kenna DT, Doherty CJ, Foweraker J, et al. (2007). Hypermutability in 78:119–46. environmental Pseudomonas aeruginosa and in populations causing Nybom SM, Salminen SJ, Meriluoto JA. (2008). Specific strains of pulmonary infection in individuals with cystic fibrosis. Microbiol 153: probiotic bacteria are efficient in removal of several different 1852–9. cyanobacterial toxins from solution. Toxicon 52:214–20. Kim J, Bae IK, Jeong SH, et al. (2011). Characterization of IncF Okeke IN, Lamikanra A, Edelman R. (1999). Socioeconomic and plasmids carrying the blaCTX-M-14 gene in clinical isolates of behavioral factors leading to acquired bacterial resistance to anti- Escherichia coli from Korea. J Antimicrob Chemother 66:1263–8. biotics in developing countries. Emerg Infect Dis 5:18–27. Kopmann C, Jechalke S, Rosendahl I, et al. (2013). Abundance and Oliver A, Levin BR, Juan C, Baquero F, Blazquez J. (2004). transferability of antibiotic resistance as related to the fate of Hypermutation and the preexistence of antibiotic-resistant For personal use only. sulfadiazine in maize rhizosphere and bulk soil. FEMS Microbiol Pseudomonas aeruginosa mutants: implications for susceptibility Ecol 83:125–34. testing and treatment of chronic infections. Antimicrob Agents Kormas KA, Lymperopoulou DS. (2013). Cyanobacterial toxin degrad- Chemother 48:4226–33. ing bacteria: who are they? BioMed Res Int 2013:463894. Available Palmer JM, Keller NP. (2010). Secondary metabolism in fungi: does from: http://dx.doi.org/10.1155/2013/463894. chromosomal location matter? Curr Opin Microbiol 13:431–6. Kumarasamy KK, Toleman MA, Walsh TR, et al. (2010). Emergence of Paulsen IT, Skurray RA, Tam R, et al. (1996). The SMR family: a novel a new antibiotic resistance mechanism in India, Pakistan, and the UK: family of multidrug efflux proteins involved with the efflux of a molecular, biological, and epidemiological study. Lancet Inf Dis 10: lipophilic drugs. Mol Microbiol 19:1167–75. 597–602. Petkovic H, Cullum J, Hranueli D, et al. (2006). Genetics of Kurihara Y, Hitomi S, Oishi T, et al. (2013). Characteristics of Streptomyces rimosus, the oxytetracycline producer. Microbiol Mol bacteremia caused by extended-spectrum beta-lactamase-producing Biol Rev 70:704–28. Proteus mirabilis. J Infect Chemother 19:799–805. Poole K. (2005). Efflux-mediated antimicrobial resistance. J Antimicrob Lee HH, Collins JC. (2012). Microbial environments confound antibiotic Chemother 56: 20–51. efficacy. Nat Chem Biol 8:6–9. Qu Y, Spain JC. (2011). Catabolic pathway for 2-nitroimidazole involves Lee LY, Hupfield T, Nicholson RL, et al. (2008). 2-Methoxycyclopentyl a novel nitrohydrolase that also confers drug resistance. Environ analogues of a Pseudomonas aeruginosa quorum sensing modulator. Microbiol 13:1010–17.

Critical Reviews in Microbiology Downloaded from informahealthcare.com by University of South Carolina on 05/29/15 Mol BioSystems 4:505–7. Rahmati S, Yang S, Davidson AL, Zechiedrich EL. (2002). Control of Liang R, Fei YJ, Prasad PD, et al. (1995). Human intestinal H+/peptide the AcrAB multidrug efflux pump by quorum-sensing regulator SdiA. cotransporter. Cloning, functional expression, and chromosomal Mol Microbiol 43:677–85. localization. J Biol Chem 270:6456–63. Rajgarhia VB, Strohl WR. (1997). Minimal Streptomyces sp. strain C5 Liebert CA, Hall RM, Summers AO. (1999). Transposon Tn21, flagship daunorubicin polyketide biosynthesis genes required for aklanonic of the floating genome. Microbiol Mol Biol Rev 63:507–22. acid biosynthesis. J Bacteriol 179:2690–6. Lima TB, Pinto MF, Ribeiro SM, et al. (2013). Bacterial resistance Rice LB. (2012). Mechanisms of resistance and clinical relevance of mechanism: what proteomics can elucidate. FASEB J 27:1291–303. resistance to beta-lactams, glycopeptides, and fluoroquinolones. Liu B, Pop M. (2009). ARDB – antibiotic resistance genes database. Mayo Clinic Proc 87:198–208. Nucl Acids Res 37:D443–7. Robicsek A, Sahm DF, Strahilevitz J, et al. (2005). Broader distribution Maal-Bared R, Bartlett KH, Bowie WR, Hall ER. (2013). Phenotypic of plasmid-mediated quinolone resistance in the United States. antibiotic resistance of Escherichia coli and E. coli O157 isolated Antimicrob Agents Chem 49:3001–3. from water, sediment and biofilms in an agricultural watershed in Romero D, Traxler MF, Lopez D, Kolter R. (2011). Antibiotics as signal British Columbia. Sci Total Env 443:315–23. molecules. Chem Rev 111:5492–505. Magiorakos AP, Srinivasan A, Carey RB, et al. (2012). Multidrug- Sahoo KC, Tamhankar AJ, Johansson E, Lundborg CS. (2010). resistant, extensively drug-resistant and pandrug-resistant bacteria: an Antibiotic use, resistance development and environmental factors: a international expert proposal for interim standard definitions for qualitative study among healthcare professionals in Orissa, India. acquired resistance. Clin Microbiol Infect 18:268–81. BMC Pub Health 10:629. Doi: 10.1186/1471-2458-10-629. 14 Y. Woappi et al. Crit Rev Microbiol, Early Online: 1–14

Saier Jr. MH, Tam R, Reizer A, Reizer J. (1994). Two novel families of Wang G, Li X, Wang Z. (2009). APD2: the updated antimicrobial bacterial membrane proteins concerned with nodulation, cell division peptide database and its application in peptide design. Nucl Acids Res and transport. Mol Microbiol 11:841–7. 37:D933–7. Sengupta S, Chattopadhyay MK, Grossart HP. (2013). The multifaceted Wenzel M, Bandow JE. (2011). Proteomic signatures in antibiotic roles of antibiotics and antibiotic resistance in nature. Front Microbiol research. Proteomics 11:3256–68. 4:47. doi: 10.3389/fmicb.2013.00047. Williams JJ, Halvorsen EM, Dwyer EM, et al. (2011). Toxin-antitoxin Singh BK, Walker A. (2006). Microbial degradation of organophos- (TA) systems are prevalent and transcribed in clinical isolates of phorus compounds. FEMS Microbiol Rev 30:428–71. Pseudomonas aeruginosa and methicillin-resistant Staphylococcus Springman AC, Lacher DW, Wu G, et al. (2009). Selection, recombin- aureus. FEMS Microbiol Lett 322:41–50. ation, and virulence gene diversity among group B streptococcal Williams JJ, Hergenrother PJ. (2008). Exposing plasmids as the Achilles’ genotypes. J Bacteriol 191:5419–27. heel of drug-resistant bacteria. Curr Opin Chem Biol 12:389–99. Tenover FC. (2006). Mechanisms of antimicrobial resistance in bacteria. Woappi Y, Gabani P, Singh OV. (2013). Emergence of antibiotic- Am J Infect Conf 34:S3–10, discussion S64–73. producing microorganisms in residential versus recreational micro- Thomas S, Karnik S, Barai RS, et al. (2010). CAMP: a useful environments. Br Microbiol Res J 3:280–94. resource for research on antimicrobial peptides. Nucl Acids Res 38: Wright GD. (2005). Bacterial resistance to antibiotics: enzymatic D774–80. degradation and modification. Adv Drug Delivery Rev 57:1451–70. Thomson CJ, Amyes SG. (1992). TRC-1: emergence of a clavulanic Xin Z, Gang W, Wei C. (2012). Isolation, identification and character- acid-resistant TEM beta-lactamase in a clinical strain. FEMS ization of human intestinal bacteria with the ability to utilize Microbiol Letters 70:113–17. chloramphenicol as the sole source of carbon and energy. FEMS Torres-Cortes G, Millan V, Ramirez-Saad HC, et al. (2011). Microbiol Ecol 82:703–12. Characterization of novel antibiotic resistance genes identified by Zaleski P, Piekarowicz A. (2004). Characterization of a dam mutant of functional metagenomics on soil samples. Environ Microbiol 13: Haemophilus influenzae Rd. Microbiol 150:3773–81. 1101–14. Zeibell K, Aguila S, Yan Shi V, et al. (2007). Mutagenesis and repair in Tsui HC, Keen SK, Sham LT, et al. (2011). Dynamic distribution of Bacillus anthracis: the effect of mutators. J Bacteriol 189:2331–8. the SecA and SecY translocase subunits and septal localization of the Zhang Q, Lambert G, Liao D, et al. (2011). Acceleration of emergence of HtrA surface chaperone/protease during Streptococcus pneumoniae bacterial antibiotic resistance in connected microenvironments. D39 cell division. MBio 2:e00202–11. Science 333:1764–7. Turner PJ, Greenhalgh JM, Edwards JR, McKellar J. (1999). Zhao-Lai D, Xi-Long L, Peng-Bin X, et al. (2012). Regulatory role for l- The MYSTIC (meropenem yearly susceptibility test information arginine in the utilization of amino acids by pig small-intestinal collection) programme. Int J Antimicrob Agents 13:117–25. bacteria. Amino Acids 43:233–44. Walsh F, Amyes SG, Duffy B. (2013). Challenging the concept Zhongli C, Shunpeng L, Guoping F. (2001). Isolation of methyl of bacteria subsisting on antibiotics. Int J Antimicrob Agents 41: parathion-degrading strain M6 and cloning of the methyl parathion 558–63. hydrolase gene. Appl Environ Microbiol 67:4922–5. For personal use only. Critical Reviews in Microbiology Downloaded from informahealthcare.com by University of South Carolina on 05/29/15