Antibiotic-resistant bacteria, which are a serious threat to the treatment of bacterial diseases, arise as a result of exposure to antibiotics in clinical and agricultural settings. However, antibiotic resistance genes are also naturally present in microbial communities regardless of human influence. Research is needed to understand the emergence and spread of resistance genes among all environments.
Antibiotic resistance in bacteria that are associated with wild animals is correlated with the proximity of the animals (and the bacteria) to human populations. Wild animals, and migratory wild birds in particular, are important contributors to the widespread dissemination of antibiotic resistance genes.
Microbial communities harbour antibiotic-resistant bacteria regardless of the human use of antibiotics, as evidenced by the presence of novel mechanisms of resistance and phylogenetically divergent resistance genes in unpolluted soil microbial communities.
Resistance to antibiotics may be a side effect of the original function of certain gene products, such as efflux pumps. Understanding the function of these gene products in natural microbial communities may uncover new ways of inhibiting the development of resistance in pathogens.
The roles of so-called antibiotic resistance genes in natural microbial communities is unknown, although potential roles include antibiotic resistance, metabolic diversification and signal disruption. The fitness conferred by resistance genes to bacteria in their native hosts and habitats needs further study.
Future work should focus on standardizing the methods used to acquire data about environmental antibiotic resistance genes and on understanding the many factors affecting the spread of antibiotic resistance genes.
Antibiotic-resistant pathogens are profoundly important to human health, but the environmental reservoirs of resistance determinants are poorly understood. The origins of antibiotic resistance in the environment is relevant to human health because of the increasing importance of zoonotic diseases as well as the need for predicting emerging resistant pathogens. This Review explores the presence and spread of antibiotic resistance in non-agricultural, non-clinical environments and demonstrates the need for more intensive investigation on this subject.
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Enright, M. C. The evolution of a resistant pathogen – the case of MRSA. Curr. Opin. Pharmacol. 3, 474–479 (2003).
Conway, S. P., Brownlee, K. G., Denton, M. & Peckham, D. G. Antibiotic treatment of multidrug-resistant organisms in cystic fibrosis. Am. J. Respir. Med. 2, 321–332 (2003).
Austin, D. J., Kristinsson, K. G. & Anderson, R. M. The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance. Proc. Natl Acad. Sci. USA 96, 1152–1156 (1999).
Weigel, L. M. et al. Genetic analysis of a high-level vancomycin-resistant isolate of Staphylococcus aureus. Science 302, 1569–1571 (2003).
Thomas, C. M. & Nielsen, K. M. Mechanisms of, and barriers to, horizontal gene transfer between bacteria. Nature Rev. Microbiol. 3, 711–721 (2005). Bacteria have many mechanisms of DNA exchange, which are clearly and thoroughly discussed in this review.
Witte, W. Medical consequences of antibiotic use in agriculture. Science 279, 996–997 (1998).
Aarestrup, F. M. Veterinary drug usage and antimicrobial resistance in bacteria of animal origin. Basic Clin. Pharmacol. Toxicol. 96, 271–281 (2005).
Salyers, A. A., Gupta, A. & Wang, Y. Human intestinal bacteria as reservoirs for antibiotic resistance genes. Trends Microbiol. 12, 412–416 (2004). The complex microbial community of the human gut and the part it plays in gene transfer are comprehensively reviewed in this outstanding article, despite the challenges of drawing conclusions from such a diverse ecosystem.
Levy, S. B. & O'Brien, T. F. Global antimicrobial resistance alerts and implications. Clin. Infect. Dis. 41, S219–S220 (2005). A concise but powerful message about the worldwide status of antibiotic resistance in pathogens.
Davies, J. Unanswered questions concerning antibiotic resistance. Clin. Microbiol. Infect. 4, 2–3 (1998).
Davies, J. Microbes have the last word. EMBO Rep. 8, 616–621 (2007).
Sarmah, A. K., Meyer, M. T. & Boxall, A. B. A global perspective on the use, sales, exposure pathways, occurrence, fate and effects of veterinary antibiotics (VAs) in the environment. Chemosphere 65, 725–759 (2006). A thorough review of the current use of antibiotics in agriculture.
Thiele-Bruhn, S. Pharmaceutical antibiotic compounds in soils - a review. J. Plant Nutr. Soil Sci. 166, 145–167 (2003).
Segura, P. A., Francois, M., Gagnon, C. & Sauve, S. Review of the occurrence of anti-infectives in contaminated wastewaters and natural and drinking waters. Environ. Health Perspect. 117, 675–684 (2009).
Cabello, F. C. Heavy use of prophylactic antibiotics in aquaculture: a growing problem for human and animal health and for the environment. Environ. Microbiol. 8, 1137–1144 (2006).
Rhodes, G. et al. Distribution of oxytetracycline resistance plasmids between aeromonads in hospital and aquaculture environments: implication of Tn 1721 in dissemination of the tetracycline resistance determinant Tet A. Appl. Environ. Microbiol. 66, 3883–3890 (2000).
Martin, M. F. & Liras, P. Organization and expression of genes involved in the biosynthesis of antibiotics and other secondary metabolites. Annu. Rev. Microbiol. 43, 173–206 (1989).
Hopwood, D. A. How do antibiotic-producing bacteria ensure their self-resistance before antibiotic biosynthesis incapacitates them? Mol. Microbiol. 63, 937–940 (2007).
Tahlan, K. et al. Initiation of actinorhodin export in Streptomyces coelicolor. Mol. Microbiol. 63, 951–961 (2007).
Benveniste, R. & Davies, J. Aminoglycoside antibiotic-inactivating enzymes in actinomycetes similar to those present in clinical isolates of antibiotic-resistant bacteria. Proc. Natl Acad. Sci. USA 70, 2276–2280 (1973). Antibiotic-resistant pathogens can arise rapidly in response to treatment with antibiotics, but the origin of the resistance is often unknown. This is one of the first reports of an origin for some resistance genes: the producers of the antibiotic.
Hermansson, M., Jones, G. W. & Kjelleberg, S. Frequency of antibiotic and heavy metal resistance, pigmentation, and plasmids in bacteria of the marine air-water interface. Appl. Environ. Microbiol. 53, 2338–2342 (1987).
Piepersberg, W., Distler, J., Heinzel, P. & Perez-Gonzalez, J. Antibiotic resistance by modification: many resistance genes could be derived from cellular control genes in actinomycetes. – A hypothesis. Actinomycetol. 2, 83–98 (1988).
Nies, D. H. Efflux-mediated heavy metal resistance in prokaryotes. FEMS Microbiol. Rev. 27, 313–339 (2003).
Poole, K. Efflux-mediated antimicrobial resistance. J. Antimicrob. Chemother. 56, 20–51 (2005).
Kadavy, D. R., Hornby, J. M., Haverkost, T. & Nickerson, K. W. Natural antibiotic resistance of bacteria isolated from larvae of the oil fly, Helaeomyia petrolei. Appl. Environ. Microbiol. 66, 4615–4619 (2000).
Allen, H. K. et al. Resident microbiota of the gypsy moth midgut harbors antibiotic resistance determinants. DNA Cell Biol. 28, 109–117 (2009).
Groh, J. L., Luo, Q., Ballard, J. D. & Krumholz, L. R. Genes that enhance the ecological fitness of Shewanella oneidensis MR-1 in sediments reveal the value of antibiotic resistance. Appl. Environ. Microbiol. 73, 492–498 (2007). So-called antibiotic resistance genes play non-resistance roles in an organism's natural habitat, and this is one of the first reports of both resistance and fitness functions for the same gene product.
Martinez, J. L. et al. Functional role of bacterial multidrug efflux pumps in microbial natural ecosystems. FEMS Microbiol. Rev. 33, 430–449 (2009).
Rosas, I. et al. Urban dust fecal pollution in Mexico City: antibiotic resistance and virulence factors of Escherichia coli. Int. J. Hyg. Environ. Health 209, 461–470 (2006).
Gandara, A. et al. Isolation of Staphylococcus aureus and antibiotic-resistant Staphylococcus aureus from residential indoor bioaerosols. Environ. Health Perspect. 114, 1859–1864 (2006).
Diaz-Mejia, J. J., Amabile-Cuevas, C. F., Rosas, I. & Souza, V. An analysis of the evolutionary relationships of integron integrases, with emphasis on the prevalence of class 1 integrons in Escherichia coli isolates from clinical and environmental origins. Microbiology 154, 94–102 (2008).
Baquero, F., Martinez, J. L. & Canton, R. Antibiotics and antibiotic resistance in water environments. Curr. Opin. Biotechnol. 19, 260–265 (2008). This review examines the source and fate of antibiotics and resistance genes in aquatic environments and is unique in its integrated perspective of the two.
Kellogg, C. A. & Griffin, D. W. Aerobiology and the global transport of desert dust. Trends Ecol. Evol. 21, 638–644 (2006).
Gilliver, M. A., Bennett, M., Begon, M., Hazel, S. M. & Hart, C. A. Antibiotic resistance found in wild rodents. Nature 401, 233–234 (1999).
Osterblad, M., Norrdahl, K., Korpimaki, E. & Huovinen, P. Antibiotic resistance. How wild are wild mammals? Nature 409, 37–38 (2001).
Souza, V., Rocha, M., Valera, A. & Eguiarte, L. E. Genetic structure of natural populations of Escherichia coli in wild hosts on different continents. Appl. Environ. Microbiol. 65, 3373–3385 (1999).
Rolland, R. M., Hausfater, G., Marshall, B. & Levy, S. B. Antibiotic-resistant bacteria in wild primates: increased prevalence in baboons feeding on human refuse. Appl. Environ. Microbiol. 49, 791–794 (1985).
Rwego, I. B., Isabirye-Basuta, G., Gillespie, T. R. & Goldberg, T. L. Gastrointestinal bacterial transmission among humans, mountain gorillas, and livestock in Bwindi Impenetrable National Park, Uganda. Conserv. Biol. 22, 1600–1607 (2008).
Cole, D. et al. Free-living Canada geese and antimicrobial resistance. Emerg. Infect. Dis. 11, 935–938 (2005).
Dolejska, M., Cizek, A. & Literak, I. High prevalence of antimicrobial-resistant genes and integrons in Escherichia coli isolates from black-headed gulls in the Czech Republic. J. Appl. Microbiol. 103, 11–19 (2007).
Sjolund, M. et al. Dissemination of multidrug-resistant bacteria into the Arctic. Emerg. Infect. Dis. 14, 70–72 (2008).
Skurnik, D. et al. Effect of human vicinity on antimicrobial resistance and integrons in animal faecal Escherichia coli. J. Antimicrob. Chemother. 57, 1215–1219 (2006).
Guardabassi, L., Schwarz, S. & Lloyd, D. H. Pet animals as reservoirs of antimicrobial-resistant bacteria. J. Antimicrob. Chemother. 54, 321–332 (2004).
Walson, J. L., Marshall, B., Pokhrel, B. M., Kafle, K. K. & Levy, S. B. Carriage of antibiotic-resistant fecal bacteria in Nepal reflects proximity to Kathmandu. J. Infect. Dis. 184, 1163–1169 (2001). This well-supported study of antibiotic resistance in human bacterial isolates finds that there is a gradient of antibiotic resistance from regions of high to low human population density.
Bartoloni, A. et al. High prevalence of acquired antimicrobial resistance unrelated to heavy antimicrobial consumption. J. Infect. Dis. 189, 1291–1294 (2004).
Pallecchi, L. et al. Population structure and resistance genes in antibiotic-resistant bacteria from a remote community with minimal antibiotic exposure. Antimicrob. Agents Chemother. 51, 1179–1184 (2007).
Baker-Austin, C., Wright, M. S., Stepanauskas, R. & McArthur, J. V. Co-selection of antibiotic and metal resistance. Trends Microbiol. 14, 176–182 (2006).
Smith, D. H. R. factor infection of Escherichia coli lyophilized in 1946. J. Bacteriol. 94, 2071–2072 (1967).
Hughes, V. M. & Datta, N. Conjugative plasmids in bacteria of the 'pre-antibiotic' era. Nature 302, 725–726 (1983). In one of the few examinations of bacteria isolated before the use of antibiotics, the authors show that conjugative plasmids were indeed common before as well as during the antibiotic era.
Houndt, T. & Ochman, H. Long-term shifts in patterns of antibiotic resistance in enteric bacteria. Appl. Environ. Microbiol. 66, 5406–5409 (2000).
Pramer, D. & Starkey, R. L. Decomposition of streptomycin. Science 113, 127 (1951).
Johnsen, J. Utilization of benzylpenicillin as carbon, nitrogen and energy source by a Pseudomonas fluorescens strain. Arch. Microbiol. 115, 271–275 (1977).
Beckman, W. & Lessie, T. G. Response of Pseudomonas cepacia to β-lactam antibiotics: utilization of penicillin G as the carbon source. J. Bacteriol. 140, 1126–1128 (1979).
Kameda, Y., Kimura, Y., Toyoura, E. & Omori, T. A method for isolating bacteria capable of producing 6-aminopenicillanic acid from benzylpenicillin. Nature 191, 1122–1123 (1961).
Abd- El-Malek, Y., Monib, M. & Hazem, A. Chloramphenicol, a simultaneous carbon and nitrogen source for a Streptomyces sp. from Egyptian soil. Nature 189, 775–776 (1961). This is the first report of a bacterium 'eating' an antibiotic.
Malik, V. S. & Vining, L. C. Metabolism of chloramphenicol by the producing organism. Can. J. Microbiol. 16, 173–179 (1970).
Lingens, F. & Oltmanns, O. Isolation and characterization of a chloramphenicol-destroying bacterium. Biochim. Biophys. Acta 130, 336–344 (1966).
Dantas, G., Sommer, M. O., Oluwasegun, R. D. & Church, G. M. Bacteria subsisting on antibiotics. Science 320, 100–103 (2008).
D'Costa, V. M., McGrann, K. M., Hughes, D. W. & Wright, G. D. Sampling the antibiotic resistome. Science 311, 374–377 (2006). A selection for an antibiotic-resistant Streptomyces sp. from soil reveals diverse and novel resistance mechanisms.
Davies, J. Darwin and microbiomes. EMBO Rep. 10, 805 (2009).
Ventura, M. et al. Genomics of Actinobacteria: tracing the evolutionary history of an ancient phylum. Microbiol. Mol. Biol. Rev. 71, 495–548 (2007).
Baltz, R. H. Renaissance in antibacterial discovery from actinomycetes. Curr. Opin. Pharmacol. 8, 557–563 (2008).
Johnson, A. P. et al. The Miller volcanic spark discharge experiment. Science 322, 404 (2008).
Currie, C. R., Scott, J. A., Summerbell, R. C. & Malloch, D. Fungus-growing ants use antibiotic-producing bacteria to control garden parasites. Nature 398, 701–704 (1999).
Cafaro, M. J. & Currie, C. R. Phylogenetic analysis of mutualistic filamentous bacteria associated with fungus-growing ants. Can. J. Microbiol. 51, 441–446 (2005).
Neeno-Eckwall, E. C., Kinkel, L. L. & Schottel, J. L. Competition and antibiosis in the biological control of potato scab. Can. J. Microbiol. 47, 332–340 (2001).
Henke, J. M. & Bassler, B. L. Bacterial social engagements. Trends Cell Biol. 14, 648–656 (2004).
Kravchenko, V. V. et al. Modulation of gene expression via disruption of NF-κB signaling by a bacterial small molecule. Science 321, 259–263 (2008).
Schertzer, J. W., Boulette, M. L. & Whiteley, M. More than a signal: non-signaling properties of quorum sensing molecules. Trends Microbiol. 17, 189–195 (2009).
Davies, J., Spiegelman, G. B. & Yim, G. The world of subinhibitory antibiotic concentrations. Curr. Opin. Microbiol. 9, 445–453 (2006). This review examines the diverse dose response-related activities of antibiotics and other inhibitors and concludes that their biological activities in nature vary greatly from their activities in therapeutic applications.
Calabrese, E. J. & Baldwin, L. A. Defining hormesis. Hum. Exp. Toxicol. 21, 91–97 (2002).
Ryan, R. P. & Dow, J. M. Diffusible signals and interspecies communication in bacteria. Microbiology 154, 1845–1858 (2008).
Linares, J. F., Gustafsson, I., Baquero, F. & Martinez, J. L. Antibiotics as intermicrobial signaling agents instead of weapons. Proc. Natl Acad. Sci. USA 103, 19484–19489 (2006).
Hall, B. G. & Barlow, M. Evolution of the serine β-lactamases: past, present and future. Drug Resist. Updat. 7, 111–123 (2004).
Waters, B. & Davies, J. Amino acid variation in the GyrA subunit of bacteria potentially associated with natural resistance to fluoroquinolone antibiotics. Antimicrob. Agents Chemother. 41, 2766–2769 (1997).
Perkins, A. E. & Nicholson, W. L. Uncovering new metabolic capabilities of Bacillus subtilis using phenotype profiling of rifampin-resistant rpoB mutants. J. Bacteriol. 190, 807–814 (2008).
Tamae, C. et al. Determination of antibiotic hypersensitivity among 4,000 single-gene-knockout mutants of Escherichia coli. J. Bacteriol. 190, 5981–5988 (2008).
Duo, M., Hou, S. & Ren, D. Identifying Escherichia coli genes involved in intrinsic multidrug resistance. Appl. Microbiol. Biotechnol. 81, 731–741 (2008).
Breidenstein, E. B., Khaira, B. K., Wiegand, I., Overhage, J. & Hancock, R. E. Complex ciprofloxacin resistome revealed by screening a Pseudomonas aeruginosa mutant library for altered susceptibility. Antimicrob. Agents Chemother. 52, 4486–4491 (2008).
Fajardo, A. et al. The neglected intrinsic resistome of bacterial pathogens. PLoS ONE 3, e1619 (2008).
Gomez, M. J. & Neyfakh, A. A. Genes involved in intrinsic antibiotic resistance of Acinetobacter baylyi. Antimicrob. Agents Chemother. 50, 3562–3567 (2006).
Demaneche, S. et al. Antibiotic-resistant soil bacteria in transgenic plant fields. Proc. Natl Acad. Sci. USA 105, 3957–3962 (2008).
Song, J. S. et al. Removal of contaminating TEM-la β-lactamase gene from commercial Taq DNA polymerase. J. Microbiol. 44, 126–128 (2006).
Guardabassi, L. & Agerso, Y. Genes homologous to glycopeptide resistance vanA are widespread in soil microbial communities. FEMS Microbiol. Lett. 259, 221–225 (2006). This study is an excellent example of the use of PCR to detect antibiotic resistance genes in complex environments.
Heuer, H. et al. Gentamicin resistance genes in environmental bacteria: prevalence and transfer. FEMS Microbiol. Ecol. 42, 289–302 (2002).
Agerso, Y., Sengelov, G. & Jensen, L. B. Development of a rapid method for direct detection of tet(M) genes in soil from Danish farmland. Environ. Int. 30, 117–122 (2004).
Committee on Metagenomics: Challenges and Functional Applications, National Research Council. The new science of metagenomics: revealing the secrets of our microbial planet (National Academies Press, Washington DC, 2007). This report provides a comprehensive overview of the different methods and analyses that encompass metagenomics and speculates about their potential applications.
Riesenfeld, C. S., Goodman, R. M. & Handelsman, J. Uncultured soil bacteria are a reservoir of new antibiotic resistance genes. Environ. Microbiol. 6, 981–989 (2004). This article describes the use of functional metagenomics to discover aminoglycoside antibiotic resistance genes in a soil microbial community.
Allen, H. K., Moe, L. A., Rodbumrer, J., Gaarder, A. & Handelsman, J. Functional metagenomics reveals diverse β-lactamases in a remote Alaskan soil. ISME J. 3, 243–251 (2009).
De Souza, M. J., Nair, S., Bharathi, P. A. L. & Chandramohan, D. Metal and antibiotic-resistance in psychrotrophic bacteria from Antarctic Marine waters. Ecotoxicology 15, 379–384 (2006).
National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility Testing. Fourteenth Informational Supplement 96–130 (National Committee for Clinical Laboratory Standards, Wayne, Pennsylvania, 2004).
Chomel, B. B., Belotto, A. & Meslin, F. X. Wildlife, exotic pets, and emerging zoonoses. Emerg. Infect. Dis. 13, 6–11 (2007).
Bengis, R. G. et al. The role of wildlife in emerging and re-emerging zoonoses. Rev. Sci. Tech. 23, 497–511 (2004).
Salyers, A. A. & Amabile-Cuevas, C. F. Why are antibiotic resistance genes so resistant to elimination? Antimicrob. Agents Chemother. 41, 2321–2325 (1997). Once established in a pathogen, antibiotic resistance mutations and genes remain surprisingly stable, even in the absence of antibiotic selection. This paper discusses various aspects of this conundrum.
Rosenblatt-Farrell, N. The landscape of antibiotic resistance. Environ. Health Perspect. 117, A244–A250 (2009).
American Academy of Microbiology. Antibiotic resistance: an ecological perspective on an old problem (American Academy of Microbiology, Washington DC, 2009).
Stokes, H. W. et al. Gene cassette PCR: sequence-independent recovery of entire genes from environmental DNA. Appl. Environ. Microbiol. 67, 5240–5246 (2001).
McManus, P. S., Stockwell, V. O., Sundin, G. W. & Jones, A. L. Antibiotic use in plant agriculture. Annu. Rev. Phytopathol. 40, 443–465 (2002).
Hughes, P. & Heritage, J. in Assessing Quality and Safety of Animal Feeds (ed. Jutzi, S.) 129–152 (Food and Agriculture Organization of the United Nations, Rome, 2004).
Hernández Serrano, P. Responsible use of antibiotics in aquaculture. (Food and Agriculture Organization of the United Nations, Rome, 2005).
Dean, W. R. & Scott, H. M. Antagonistic synergy: process. and paradox in the development of new agricultural antimicrobial regulations. Agric. Human Values 22, 479–489 (2005).
J. Handelsman was supported by the US Department of Agriculture Microbial Observatories Program and J. Donato was supported by the US National Institutes of Health (grant GM876102).
The authors declare no competing financial interests.
The antibiotic resistance genotype and phenotypeof a bacterium.
Unspoiled or unpolluted by human activities.
The range of biologically active, low-molecular-mass (< 5 kDa) compounds that are produced by defined biosynthetic pathways in bacteria, yeast, plants and other organisms.
An interaction between microorganisms involving a small molecule that is produced by one organism and detrimental to the other.
A dose-dependent response phenomenon shown by bioactive compounds and drugs, such that they have contrasting activities at low (subinhibitory) and high (inhibitory) concentrations.
A compound or molecule that augments the activity of an antibiotic.
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Allen, H., Donato, J., Wang, H. et al. Call of the wild: antibiotic resistance genes in natural environments. Nat Rev Microbiol 8, 251–259 (2010). https://doi.org/10.1038/nrmicro2312
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