What is a resistance gene? Ranking risk in resistomes

Metagenomic studies have shown that antibiotic resistance genes are ubiquitous in the environment, which has led to the suggestion that there is a high risk that these genes will spread to bacteria that cause human infections. If this is true, estimating the real risk of dissemination of resistance genes from environmental reservoirs to human pathogens is therefore very difficult. In this Opinion article, we analyse the current definitions of antibiotic resistance and antibiotic resistance genes, and we describe the bottlenecks that affect the transfer of antibiotic resistance genes to human pathogens. We propose rules for estimating the risks associated with genes that are present in environmental resistomes by evaluating the likelihood of their introduction into human pathogens, and the consequences of such events for the treatment of infections.

[1]  J. Bull,et al.  Short-sighted evolution and the virulence of pathogenic microorganisms. , 1994, Trends in microbiology.

[2]  L. Piddock.  Multidrug-resistance efflux pumps ? not just for resistance , 2006, Nature Reviews Microbiology.

[3]  Fernando Baquero,et al.  Predicting antibiotic resistance , 2007, Nature Reviews Microbiology.

[4]  S. Levy,et al.  marA, a regulated locus which controls expression of chromosomal multiple antibiotic resistance in Escherichia coli , 1991, Journal of bacteriology.

[5]  E. Wellington,et al.  Coevolution of antibiotic production and counter-resistance in soil bacteria. , 2010, Environmental microbiology.

[6]  F. Baquero.  European standards for antibiotic susceptibility testing: Towards a theoretical consensus , 1990, European Journal of Clinical Microbiology and Infectious Diseases.

[7]  J. Martínez,et al.  Natural Antibiotic Resistance and Contamination by Antibiotic Resistance Determinants: The Two Ages in the Evolution of Resistance to Antimicrobials , 2012, Front. Microbio..

[8]  J. Martínez,et al.  Functional role of bacterial multidrug efflux pumps in microbial natural ecosystems. , 2009, FEMS microbiology reviews.

[9]  J. Martínez,et al.  A global view of antibiotic resistance. , 2009, FEMS microbiology reviews.

[10]  T. Baba,et al.  Genomic Basis for Methicillin Resistance in Staphylococcus aureus , 2013, Infection & chemotherapy.

[11]  M. Bibb,et al.  Novel Mechanism of Glycopeptide Resistance in the A40926 Producer Nonomuraea sp. ATCC 39727 , 2010, Antimicrobial Agents and Chemotherapy.

[12]  F J Ayala,et al.  Adaptation and novelty: teleological explanations in evolutionary biology. , 1999, History and philosophy of the life sciences.

[13]  G. Kronvall.  Normalized Resistance Interpretation as a Tool for Establishing Epidemiological MIC Susceptibility Breakpoints , 2010, Journal of Clinical Microbiology.

[14]  J Davies,et al.  Inactivation of antibiotics and the dissemination of resistance genes. , 1994, Science.

[15]  Teresa M. Coque,et al.  Antibiotic resistance shaping multi-level population biology of bacteria , 2013, Front. Microbiol..

[16]  F. Baquero.  Low-level antibacterial resistance: a gateway to clinical resistance. , 2001, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[17]  J. Martínez.  The role of natural environments in the evolution of resistance traits in pathogenic bacteria , 2009, Proceedings of the Royal Society B: Biological Sciences.

[18]  J. Marchesi,et al.  Transposon-aided capture (TRACA) of plasmids resident in the human gut mobile metagenome , 2007, Nature Methods.

[19]  U. Gophna,et al.  The complexity hypothesis revisited: connectivity rather than function constitutes a barrier to horizontal gene transfer. , 2011, Molecular biology and evolution.

[20]  G. Nair,et al.  In Silico Analysis of Antibiotic Resistance Genes in the Gut Microflora of Individuals from Diverse Geographies and Age-Groups , 2013, PloS one.

[21]  Joy Scaria,et al.  Antibiotic Resistance Genes Online (ARGO): A Database on vancomycin and βlactam resistance genes , 2005, Bioinformation.

[22]  Mihai Pop,et al.  ARDB—Antibiotic Resistance Genes Database , 2008, Nucleic Acids Res..

[23]  Timothy R. Walsh,et al.  Characterization of a New Metallo-β-Lactamase Gene, blaNDM-1, and a Novel Erythromycin Esterase Gene Carried on a Unique Genetic Structure in Klebsiella pneumoniae Sequence Type 14 from India , 2009, Antimicrobial Agents and Chemotherapy.

[24]  F. Baquero,et al.  Beyond serial passages: new methods for predicting the emergence of resistance to novel antibiotics. , 2011, Current opinion in pharmacology.

[25]  M. Sommer,et al.  Context matters - the complex interplay between resistome genotypes and resistance phenotypes. , 2012, Current opinion in microbiology.

[26]  Molly K. Gibson,et al.  Bacterial phylogeny structures soil resistomes across habitats , 2014, Nature.

[27]  R. Hancock,et al.  Characterization of the Polymyxin B Resistome of Pseudomonas aeruginosa , 2012, Antimicrobial Agents and Chemotherapy.

[28]  J. Duval,et al.  Characterization of the chromosomal aac(6')-Ii gene specific for Enterococcus faecium , 1993, Antimicrobial Agents and Chemotherapy.

[29]  H. Nikaido,et al.  Active efflux of bile salts by Escherichia coli , 1997, Journal of bacteriology.

[30]  F. Baquero,et al.  Ecology and evolution of antibiotic resistance. , 2009, Environmental microbiology reports.

[31]  R. Mackie,et al.  Evolution and ecology of antibiotic resistance genes. , 2007, FEMS microbiology letters.

[32]  P. Bennett,et al.  Evidence of Antibiotic Resistance Gene Silencing in Escherichia coli , 2006, Antimicrobial Agents and Chemotherapy.

[33]  Johan W Mouton,et al.  European harmonization of MIC breakpoints for antimicrobial susceptibility testing of bacteria. , 2003, The Journal of antimicrobial chemotherapy.

[34]  K. Young,et al.  AmpC and AmpH, proteins related to the class C beta-lactamases, bind penicillin and contribute to the normal morphology of Escherichia coli , 1997, Journal of bacteriology.

[35]  J. Martínez,et al.  A Function of SmeDEF, the Major Quinolone Resistance Determinant of Stenotrophomonas maltophilia, Is the Colonization of Plant Roots , 2014, Applied and Environmental Microbiology.

[36]  F. Weill,et al.  Six Groups of the OXY β-Lactamase Evolved over Millions of Years in Klebsiella oxytoca , 2005, Antimicrobial Agents and Chemotherapy.

[37]  M. Ragan,et al.  Lateral genetic transfer and the construction of genetic exchange communities. , 2011, FEMS microbiology reviews.

[38]  J. Martínez,et al.  Bottlenecks in the Transferability of Antibiotic Resistance from Natural Ecosystems to Human Bacterial Pathogens , 2011, Front. Microbio..

[39]  Mark R. Liles,et al.  Identification of Diverse Antimicrobial Resistance Determinants Carried on Bacterial, Plasmid, or Viral Metagenomes from an Activated Sludge Microbial Assemblage , 2010, Applied and Environmental Microbiology.

[40]  Lisa M. Durso,et al.  Distribution and Quantification of Antibiotic Resistant Genes and Bacteria across Agricultural and Non-Agricultural Metagenomes , 2012, PloS one.

[41]  R. Humphries,et al.  The emerging problem of linezolid-resistant Staphylococcus. , 2013, The Journal of antimicrobial chemotherapy.

[42]  R. Hakenbeck,et al.  Mosaic pbpX genes of major clones of penicillin‐resistant Streptococcus pneumoniae have evolved from pbpX genes of a penicillin‐sensitive Streptococcus oralis , 1994, Molecular microbiology.

[43]  Molly K. Gibson,et al.  Improved annotation of antibiotic resistance determinants reveals microbial resistomes cluster by ecology , 2014, The ISME Journal.

[44]  B. Levin,et al.  Compensatory mutations, antibiotic resistance and the population genetics of adaptive evolution in bacteria. , 2000, Genetics.

[45]  G. Dantas,et al.  The Shared Antibiotic Resistome of Soil Bacteria and Human Pathogens , 2012, Science.

[46]  Jian Wang,et al.  Metagenome-wide analysis of antibiotic resistance genes in a large cohort of human gut microbiota , 2013, Nature Communications.

[47]  B. Murray,et al.  Genes involved in the regulation of beta-lactamase production in enterococci and staphylococci , 1993, Antimicrobial Agents and Chemotherapy.

[48]  Timothy R. Walsh,et al.  Tackling antibiotic resistance , 2011, Nature Reviews Microbiology.

[49]  D. Balkwill,et al.  Antibiotic Resistance in Bacteria Isolated from the Deep Terrestrial Subsurface , 2009, Microbial Ecology.

[50]  G. B. Golding,et al.  Antibiotic resistance is ancient , 2011, Nature.

[51]  J. Liñares,et al.  Horizontal Transfer of parC and gyrA in Fluoroquinolone-Resistant Clinical Isolates ofStreptococcus pneumoniae , 2000, Antimicrobial Agents and Chemotherapy.

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

[53]  Peer Bork,et al.  Country-specific antibiotic use practices impact the human gut resistome , 2013, Genome research.

[54]  F. Baquero,et al.  Mutation Frequencies and Antibiotic Resistance , 2000, Antimicrobial Agents and Chemotherapy.

[55]  D. Andersson,et al.  Persistence of antibiotic resistance in bacterial populations. , 2011, FEMS microbiology reviews.

[56]  H. Nikaido,et al.  Role of mexA-mexB-oprM in antibiotic efflux in Pseudomonas aeruginosa , 1995, Antimicrobial agents and chemotherapy.

[57]  Edward Topp,et al.  The scourge of antibiotic resistance: the important role of the environment. , 2013, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[58]  J. Oliveros,et al.  Interplay between intrinsic and acquired resistance to quinolones in Stenotrophomonas maltophilia. , 2014, Environmental microbiology.

[59]  R. Hancock,et al.  Genetic Determinants Involved in the Susceptibility of Pseudomonas aeruginosa to β-Lactam Antibiotics , 2010, Antimicrobial Agents and Chemotherapy.

[60]  P. Silley,et al.  Potential confusion regarding the term 'resistance' in epidemiological surveys. , 2007, The Journal of antimicrobial chemotherapy.

[61]  Heather K. Allen,et al.  Call of the wild: antibiotic resistance genes in natural environments , 2010, Nature Reviews Microbiology.

[62]  L. Friedrich,et al.  Vancomycin MIC creep in non-vancomycin-intermediate Staphylococcus aureus (VISA), vancomycin-susceptible clinical methicillin-resistant S. aureus (MRSA) blood isolates from 2001-05. , 2007, The Journal of antimicrobial chemotherapy.

[63]  Fernando Baquero,et al.  The Neglected Intrinsic Resistome of Bacterial Pathogens , 2008, PloS one.

[64]  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.

[65]  Peter Spanogiannopoulos,et al.  A rifamycin inactivating phosphotransferase family shared by environmental and pathogenic bacteria , 2014, Proceedings of the National Academy of Sciences.

[66]  Alison K. Hottes,et al.  Genetic Architecture of Intrinsic Antibiotic Susceptibility , 2009, PloS one.

[67]  F. Baquero,et al.  Metagenomic epidemiology: a public health need for the control of antimicrobial resistance. , 2012, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

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

[69]  J. Martínez,et al.  Differential Epigenetic Compatibility of qnr Antibiotic Resistance Determinants with the Chromosome of Escherichia coli , 2012, PloS one.

[70]  Kevin Outterson,et al.  Fighting antibiotic resistance: marrying new financial incentives to meeting public health goals. , 2010, Health affairs.

[71]  Jesper V Olsen,et al.  Pathogens and host immunity in the ancient human oral cavity , 2014, Nature Genetics.

[72]  J. Davies,et al.  Origins and Evolution of Antibiotic Resistance , 1996, Microbiology and Molecular Biology Reviews.

[73]  H. Goossens,et al.  Antibiotic resistance—the need for global solutions , 2013, BDJ.

[74]  J. Collins,et al.  Antibiotic Treatment Expands the Resistance Reservoir and Ecological Network of the Phage Metagenome , 2013, Nature.

[75]  F. Rojo,et al.  Overproduction of the multidrug efflux pump MexEF-OprN does not impair Pseudomonas aeruginosa fitness in competition tests, but produces specific changes in bacterial regulatory networks. , 2012, Environmental microbiology.

[76]  S. Rasmussen,et al.  Identification of acquired antimicrobial resistance genes , 2012, The Journal of antimicrobial chemotherapy.

[77]  I. Morrissey,et al.  Evaluation of Epidemiological Cut-Off Values Indicates that Biocide Resistant Subpopulations Are Uncommon in Natural Isolates of Clinically-Relevant Microorganisms , 2014, PloS one.

[78]  Diarmaid Hughes,et al.  Antibiotic resistance and its cost: is it possible to reverse resistance? , 2010, Nature Reviews Microbiology.

[79]  P. Nordmann,et al.  Plasmid-mediated quinolone resistance in Aeromonas allosaccharophila recovered from a Swiss lake. , 2008, The Journal of antimicrobial chemotherapy.