The human microbiome harbors a diverse reservoir of antibiotic resistance genes

The increasing levels of multi-drug resistance in human pathogenic bacteria are compromising our ability to treat infectious disease. Since antibiotic resistance determinants are readily exchanged between bacteria through lateral gene transfer, there is an increasing interest in investigating reservoirs of antibiotic resistance accessible to pathogens. Due to the high likelihood of contact and genetic exchange with pathogens during disease progression, the human microflora warrants special attention as perhaps the most accessible reservoir of resistance genes. Indeed, numerous previous studies have demonstrated substantial antibiotic resistance in cultured isolates from the human microflora. By applying metagenomic functional selections, we recently demonstrated that the functional repertoire of resistance genes in the human microbiome is much more diverse than suggested using previous culture-dependent methods. We showed that many resistance genes from cultured proteobacteria from human fecal samples are identical to resistance genes harbored by human pathogens, providing strong support for recent genetic exchange of this resistance machinery. In contrast, most of the resistance genes we identified with culture independent metagenomic sampling from the same samples were novel when compared to all known genes in public databases. While this clearly demonstrates that the antibiotic resistance reservoir of the large fraction of the human microbiome recalcitrant to culturing is severely under sampled, it may also suggest that barriers exist to lateral gene transfer between these bacteria and readily cultured human pathogens. If we hope to turn the tide against multidrug resistant infections, we must urgently commit to quantitatively characterizing the resistance reservoirs encoded by our diverse human microbiomes, with a particular focus on routes of exchange of these reservoirs with other microbial communities.

[1]  Heather K. Allen,et al.  Functional metagenomics reveals diverse β-lactamases in a remote Alaskan soil , 2009, The ISME Journal.

[2]  C. Walsh.  Molecular mechanisms that confer antibacterial drug resistance , 2000, Nature.

[3]  Vincent B. Young,et al.  Antibiotic-Associated Diarrhea Accompanied by Large-Scale Alterations in the Composition of the Fecal Microbiota , 2004, Journal of Clinical Microbiology.

[4]  P. Bork,et al.  A human gut microbial gene catalogue established by metagenomic sequencing , 2010, Nature.

[5]  T. Vogel,et al.  Antibiotic-resistant soil bacteria in transgenic plant fields , 2008, Proceedings of the National Academy of Sciences.

[6]  Frank Møller Aarestrup,et al.  Effect of Abolishment of the Use of Antimicrobial Agents for Growth Promotion on Occurrence of Antimicrobial Resistance in Fecal Enterococci from Food Animals in Denmark , 2001, Antimicrobial Agents and Chemotherapy.

[7]  P. Trieu-Cuot,et al.  Inducible transfer of conjugative transposon Tn1545 from Enterococcus faecalis to Listeria monocytogenes in the digestive tracts of gnotobiotic mice , 1991, Antimicrobial Agents and Chemotherapy.

[8]  J. Krieger,et al.  Distribution and mobility of the tetracycline resistance determinant tetQ. , 1997, The Journal of antimicrobial chemotherapy.

[9]  D. Hughes,et al.  Sampling the Antibiotic Resistome , 2006, Science.

[10]  Yanping Wang,et al.  Human intestinal bacteria as reservoirs for antibiotic resistance genes. , 2004, Trends in microbiology.

[11]  M. Kuskowski,et al.  Antimicrobial Drug–Resistant Escherichia coli from Humans and Poultry Products, Minnesota and Wisconsin, 2002–2004 , 2007, Emerging infectious diseases.

[12]  E. Purdom,et al.  Diversity of the Human Intestinal Microbial Flora , 2005, Science.

[13]  S. Falkow,et al.  A single genetic locus encoded by Yersinia pseudotuberculosis permits invasion of cultured animal cells by Escherichia coli K-12 , 1985, Nature.

[14]  R. Ley,et al.  Ecological and Evolutionary Forces Shaping Microbial Diversity in the Human Intestine , 2006, Cell.

[15]  I. Rigoutsos,et al.  Accurate phylogenetic classification of variable-length DNA fragments , 2007, Nature Methods.

[16]  J. Handelsman,et al.  Uncultured soil bacteria are a reservoir of new antibiotic resistance genes. , 2004, Environmental microbiology.

[17]  D. Relman,et al.  An ecological and evolutionary perspective on human–microbe mutualism and disease , 2007, Nature.

[18]  G. Church,et al.  Bacteria Subsisting on Antibiotics , 2007, Science.

[19]  Jeremy K. Nicholson,et al.  Gut microbiota: a potential new territory for drug targeting , 2008, Nature Reviews Drug Discovery.

[20]  J Davies,et al.  Aminoglycoside antibiotic-inactivating enzymes in actinomycetes similar to those present in clinical isolates of antibiotic-resistant bacteria. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[21]  M. Woodward,et al.  A high prevalence of antimicrobial resistant Escherichia coli isolated from pigs and a low prevalence of antimicrobial resistant E. coli from cattle and sheep in Great Britain at slaughter. , 2008, FEMS microbiology letters.

[22]  Gerard D. Wright,et al.  Expanding the soil antibiotic resistome: exploring environmental diversity. , 2007, Current opinion in microbiology.

[23]  H. Gilbert,et al.  Gene Transfer in the Gastrointestinal Tract , 1999, Applied and Environmental Microbiology.

[24]  M. Pop,et al.  Metagenomic Analysis of the Human Distal Gut Microbiome , 2006, Science.

[25]  G. Church,et al.  Functional Characterization of the Antibiotic Resistance Reservoir in the Human Microflora , 2009, Science.

[26]  Hilary G. Morrison,et al.  Reproducible Community Dynamics of the Gastrointestinal Microbiota following Antibiotic Perturbation , 2009, Infection and Immunity.

[27]  Wei Zhang,et al.  Vibrio cholerae O139 Multiple-Drug Resistance Mediated by Yersinia pestis pIP1202-Like Conjugative Plasmids , 2008, Antimicrobial Agents and Chemotherapy.