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.

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Figure 1: Determination of epidemiological breakpoints of susceptibility to antibiotics.
Figure 2: Ranking the risks of detection of resistance genes in resistomes.


  1. 1

    World Health Organization. Antimicrobial Resistance: Global Report on Surveillance. (WHO Press, 2014).

  2. 2

    Kesselheim, A. S. & Outterson, K. Fighting antibiotic resistance: marrying new financial incentives to meeting public health goals. Health Aff. (Millwood) 29, 1689–1696 (2010).

    Google Scholar 

  3. 3

    Baquero, F. Metagenomic epidemiology: a public health need for the control of antimicrobial resistance. Clin. Microbiol. Infect. 18 (Suppl. 4), 67–73 (2012).

    CAS  PubMed  Google Scholar 

  4. 4

    Allen, H. K. et al. Call of the wild: antibiotic resistance genes in natural environments. Nature Rev. Microbiol. 8, 251–259 (2010).

    CAS  Google Scholar 

  5. 5

    Forsberg, K. J. et al. The shared antibiotic resistome of soil bacteria and human pathogens. Science 337, 1107–1111 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Sommer, M. O., Dantas, G. & Church, G. M. Functional characterization of the antibiotic resistance reservoir in the human microflora. Science 325, 1128–1131 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    D'Costa, V. M., McGrann, K. M., Hughes, D. W. & Wright, G. D. Sampling the antibiotic resistome. Science 311, 374–377 (2006).

    CAS  PubMed  Google Scholar 

  8. 8

    Ghosh, T. S., Gupta, S. S., Nair, G. B. & Mande, S. S. In silico analysis of antibiotic resistance genes in the gut microflora of individuals from diverse geographies and age-groups. PLoS ONE 8, e83823 (2013).

    PubMed  PubMed Central  Google Scholar 

  9. 9

    Hu, Y. et al. Metagenome-wide analysis of antibiotic resistance genes in a large cohort of human gut microbiota. Nature Commun. 4, 2151 (2013).

    Google Scholar 

  10. 10

    Durso, L. M., Miller, D. N. & Wienhold, B. J. Distribution and quantification of antibiotic resistant genes and bacteria across agricultural and non-agricultural metagenomes. PLoS ONE 7, e48325 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    D'Costa, V. M. et al. Antibiotic resistance is ancient. Nature 477, 457–461 (2011).

    CAS  PubMed  Google Scholar 

  12. 12

    Finley, R. L. et al. The scourge of antibiotic resistance: the important role of the environment. Clin. Infect. Dis. 57, 704–710 (2013).

    PubMed  Google Scholar 

  13. 13

    Ferrandiz, M. J., Fenoll, A., Linares, J. & De La Campa, A. G. Horizontal transfer of parC and gyrA in fluoroquinolone-resistant clinical isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 44, 840–847 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Baquero, F., Alvarez-Ortega, C. & Martinez, J. L. Ecology and evolution of antibiotic resistance. Environ. Microbiol. Rep. 1, 469–476 (2009).

    CAS  PubMed  Google Scholar 

  15. 15

    Martinez, J. L. & Baquero, F. Mutation frequencies and antibiotic resistance. Antimicrob. Agents Chemother. 44, 1771–1777 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Laxminarayan, R. et al. Antibiotic resistance — the need for global solutions. Lancet Infect. Dis. 13, 1057–1098 (2013).

    PubMed  Google Scholar 

  17. 17

    Bush, K. et al. Tackling antibiotic resistance. Nature Rev. Microbiol. 9, 894–896 (2011).

    CAS  Google Scholar 

  18. 18

    Baquero, F. Low-level antibacterial resistance: a gateway to clinical resistance. Drug Resist. Updat. 4, 93–105 (2001).

    CAS  PubMed  Google Scholar 

  19. 19

    Baquero, F. European standards for antibiotic susceptibility testing: towards a theoretical consensus. Eur. J. Clin. Microbiol. Infect. Dis. 9, 492–495 (1990).

    CAS  PubMed  Google Scholar 

  20. 20

    Kronvall, G. Normalized resistance interpretation as a tool for establishing epidemiological MIC susceptibility breakpoints. J. Clin. Microbiol. 48, 4445–4452 (2010).

    PubMed  PubMed Central  Google Scholar 

  21. 21

    Kahlmeter, G. et al. European harmonization of MIC breakpoints for antimicrobial susceptibility testing of bacteria. J. Antimicrob. Chemother. 52, 145–148 (2003).

    CAS  PubMed  Google Scholar 

  22. 22

    Simjee, S., Silley, P., Werling, H. O. & Bywater, R. Potential confusion regarding the term 'resistance' in epidemiological surveys. J. Antimicrob. Chemother. 61, 228–229 (2008).

    CAS  PubMed  Google Scholar 

  23. 23

    Morrissey, I. et al. Evaluation of epidemiological cut-off values indicates that biocide resistant subpopulations are uncommon in natural isolates of clinically-relevant microorganisms. PLoS ONE 9, e86669 (2014).

    PubMed  PubMed Central  Google Scholar 

  24. 24

    Garcia-Leon, G., Salgado, F., Oliveros, J. C., Sanchez, M. B. & Martinez, J. L. Interplay between intrinsic and acquired resistance to quinolones in Stenotrophomonas maltophilia. Environ. Microbiol. 16, 1282–1296 (2014).

    CAS  PubMed  Google Scholar 

  25. 25

    Alvarez-Ortega, C., Wiegand, I., Olivares, J., Hancock, R. E. & Martinez, J. L. Genetic determinants involved in the susceptibility of Pseudomonas aeruginosa to ß-lactam antibiotics. Antimicrob. Agents Chemother. 54, 4159–4167 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Girgis, H. S., Hottes, A. K. & Tavazoie, S. Genetic architecture of intrinsic antibiotic susceptibility. PLoS ONE 4, e5629 (2009).

    PubMed  PubMed Central  Google Scholar 

  27. 27

    Fajardo, A. et al. The neglected intrinsic resistome of bacterial pathogens. PLoS ONE 3, e1619 (2008).

    PubMed  PubMed Central  Google Scholar 

  28. 28

    Fernandez, L. et al. Characterization of the polymyxin B resistome of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 57, 110–119 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Forsberg, K. J. et al. Bacterial phylogeny structures soil resistomes across habitats. Nature 509, 612–616 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Parsley, L. C. et al. Identification of diverse antimicrobial resistance determinants carried on bacterial, plasmid, or viral metagenomes from an activated sludge microbial assemblage. Appl. Environ. Microbiol. 76, 3753–3757 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Zankari, E. et al. Identification of acquired antimicrobial resistance genes. J. Antimicrob. Chemother. 67, 2640–2644 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Scaria, J., Chandramouli, U. & Verma, S. K. Antibiotic Resistance Genes Online (ARGO): a database on vancomycin and ß-lactam resistance genes. Bioinformation 1, 5–7 (2005).

    PubMed  PubMed Central  Google Scholar 

  33. 33

    Modi, S. R., Lee, H. H., Spina, C. S. & Collins, J. J. Antibiotic treatment expands the resistance reservoir and ecological network of the phage metagenome. Nature 499, 219–222 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Liu, B. & Pop, M. ARDB — Antibiotic Resistance Genes Database. Nucleic Acids Res. 37, D443–D447 (2009).

    CAS  PubMed  Google Scholar 

  35. 35

    Forslund, K. et al. Country-specific antibiotic use practices impact the human gut resistome. Genome Res. 23, 1163–1169 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Davies, J. Inactivation of antibiotics and the dissemination of resistance genes. Science 264, 375–382 (1994).

    CAS  PubMed  Google Scholar 

  37. 37

    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).

    CAS  PubMed  Google Scholar 

  38. 38

    Martinez, J. L. et al. A global view of antibiotic resistance. FEMS Microbiol. Rev. 33, 44–65 (2009).

    CAS  PubMed  Google Scholar 

  39. 39

    Martinez, J. L. et al. Functional role of bacterial multidrug efflux pumps in microbial natural ecosystems. FEMS Microbiol. Rev. 33, 430–449 (2009).

    CAS  PubMed  Google Scholar 

  40. 40

    Piddock, L. J. Multidrug-resistance efflux pumps — not just for resistance. Nature Rev. Microbiol. 4, 629–636 (2006).

    CAS  Google Scholar 

  41. 41

    Garcia-Leon, G. et al. A function of SmeDEF, the major quinolone resistance determinant of Stenotrophomonas maltophilia, is the colonization of the roots of the plants. Appl. Environ. Microbiol. http://dx.doi.org/10.1128/AEM.01058-14 (2014).

  42. 42

    Thanassi, D. G., Cheng, L. W. & Nikaido, H. Active efflux of bile salts by Escherichia coli. J. Bacteriol. 179, 2512–2518 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Henderson, T. A., Young, K. D., Denome, S. A. & Elf, P. K. AmpC and AmpH, proteins related to the class C ß-lactamases, bind penicillin and contribute to the normal morphology of Escherichia coli. J. Bacteriol. 179, 6112–6121 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Ayala, F. J. Adaptation and novelty: teleological explanations in evolutionary biology. Hist. Philos. Life Sci. 21, 3–33 (1999).

    CAS  PubMed  Google Scholar 

  45. 45

    Laskaris, P., Tolba, S., Calvo-Bado, L. & Wellington, L. Coevolution of antibiotic production and counter-resistance in soil bacteria. Environ. Microbiol. 12, 783–796 (2010).

    CAS  PubMed  Google Scholar 

  46. 46

    Hiramatsu, K. et al. Genomic basis for methicillin resistance in Staphylococcus aureus. Infect. Chemother. 45, 117–136 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Martinez, J. L. Natural antibiotic resistance and contamination by antibiotic resistance determinants: the two ages in the evolution of resistance to antimicrobials. Front. Microbiol. 3, 1 (2012).

    PubMed  PubMed Central  Google Scholar 

  48. 48

    Martinez, J. L. The role of natural environments in the evolution of resistance traits in pathogenic bacteria. Proc. Biol. Sci. 276, 2521–2530 (2009).

    PubMed  PubMed Central  Google Scholar 

  49. 49

    Martinez, J. L., Baquero, F. & Andersson, D. I. Predicting antibiotic resistance. Nature Rev. Microbiol. 5, 958–965 (2007).

    CAS  Google Scholar 

  50. 50

    Hachler, H., Cohen, S. P. & Levy, S. B. marA, a regulated locus which controls expression of chromosomal multiple antibiotic resistance in Escherichia coli. J. Bacteriol. 173, 5532–5538 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Li, X. Z., Nikaido, H. & Poole, K. Role of MexA–MexB –OprM in antibiotic efflux in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 39, 1948–1953 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Costa, Y., Galimand, M., Leclercq, R., Duval, J. & Courvalin, P. Characterization of the chromosomal aac(6)-Ii gene specific for Enterococcus faecium. Antimicrob. Agents Chemother. 37, 1896–1903 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Fevre, C. et al. Six groups of the OXY ß-lactamase evolved over millions of years in Klebsiella oxytoca. Antimicrob. Agents Chemother. 49, 3453–3462 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Dantas, G. & Sommer, M. O. Context matters — the complex interplay between resistome genotypes and resistance phenotypes. Curr. Opin. Microbiol. 15, 577–582 (2012).

    PubMed  Google Scholar 

  55. 55

    Zscheck, K. K. & Murray, B. E. Genes involved in the regulation of ß-lactamase production in enterococci and staphylococci. Antimicrob. Agents Chemother. 37, 1966–1970 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Enne, V. I., Delsol, A. A., Roe, J. M. & Bennett, P. M. Evidence of antibiotic resistance gene silencing in Escherichia coli. Antimicrob. Agents Chemother. 50, 3003–3010 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Yong, D. et al. Characterization of a new metallo-ß-lactamase gene, blaNDM-1, and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob. Agents Chemother. 53, 5046–5054 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Picao, R. C. et al. Plasmid-mediated quinolone resistance in Aeromonas allosaccharophila recovered from a Swiss lake. J. Antimicrob. Chemother. 62, 948–950 (2008).

    CAS  PubMed  Google Scholar 

  59. 59

    Jones, B. V. & Marchesi, J. R. Transposon-aided capture (TRACA) of plasmids resident in the human gut mobile metagenome. Nature Methods 4, 55–61 (2007).

    CAS  PubMed  Google Scholar 

  60. 60

    Marcone, G. L. et al. Novel mechanism of glycopeptide resistance in the A40926 producer Nonomuraea sp. ATCC 39727. Antimicrob. Agents Chemother. 54, 2465–2472 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Gu, B., Kelesidis, T., Tsiodras, S., Hindler, J. & Humphries, R. M. The emerging problem of linezolid-resistant Staphylococcus. J. Antimicrob. Chemother. 68, 4–11 (2013).

    CAS  PubMed  Google Scholar 

  62. 62

    Spanogiannopoulos, P., Waglechner, N., Koteva, K. & Wright, G. D. A rifamycin inactivating phosphotransferase family shared by environmental and pathogenic bacteria. Proc. Natl Acad. Sci. USA 111, 7102–7107 (2014).

    CAS  PubMed  Google Scholar 

  63. 63

    Andersson, D. I. & Hughes, D. Persistence of antibiotic resistance in bacterial populations. FEMS Microbiol. Rev. 35, 901–911 (2011).

    CAS  PubMed  Google Scholar 

  64. 64

    Andersson, D. I. & Hughes, D. Antibiotic resistance and its cost: is it possible to reverse resistance? Nature Rev. Microbiol. 8, 260–271 (2010).

    CAS  Google Scholar 

  65. 65

    Brown, M. G. & Balkwill, D. L. Antibiotic resistance in bacteria isolated from the deep terrestrial subsurface. Microb. Ecol. 57, 484–493 (2009).

    CAS  PubMed  Google Scholar 

  66. 66

    Warinner, C. et al. Pathogens and host immunity in the ancient human oral cavity. Nature Genet. 46, 336–344 (2014).

    CAS  PubMed  Google Scholar 

  67. 67

    Davies, J. & Davies, D. Origins and evolution of antibiotic resistance. Microbiol. Mol. Biol. Rev. 74, 417–433 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Martinez, J. L. Bottlenecks in the transferability of antibiotic resistance from natural ecosystems to human bacterial pathogens. Front. Microbiol. 2, 265 (2011).

    PubMed  Google Scholar 

  69. 69

    Aminov, R. I. & Mackie, R. I. Evolution and ecology of antibiotic resistance genes. FEMS Microbiol. Lett. 271, 147–161 (2007).

    CAS  PubMed  Google Scholar 

  70. 70

    Skippington, E. & Ragan, M. A. Lateral genetic transfer and the construction of genetic exchange communities. FEMS Microbiol. Rev. 35, 707–735 (2011).

    CAS  PubMed  Google Scholar 

  71. 71

    Cohen, O., Gophna, U. & Pupko, T. The complexity hypothesis revisited: connectivity rather than function constitutes a barrier to horizontal gene transfer. Mol. Biol. Evol. 28, 1481–1489 (2011).

    CAS  PubMed  Google Scholar 

  72. 72

    Baquero, F., Tedim, A. P. & Coque, T. M. Antibiotic resistance shaping multi-level population biology of bacteria. Front. Microbiol. 4, 15 (2013).

    PubMed  PubMed Central  Google Scholar 

  73. 73

    Levin, B. R. & Bull, J. J. Short-sighted evolution and the virulence of pathogenic microorganisms. Trends Microbiol. 2, 76–81 (1994).

    CAS  PubMed  Google Scholar 

  74. 74

    Sibold, C. et al. Mosaic pbpX genes of major clones of penicillin-resistant Streptococcus pneumoniae have evolved from pbpX genes of a penicillin-sensitive Streptococcus oralis. Mol. Microbiol. 12, 1013–1023 (1994).

    CAS  PubMed  Google Scholar 

  75. 75

    Martinez, J. L., Baquero, F. & Andersson, D. I. Beyond serial passages: new methods for predicting the emergence of resistance to novel antibiotics. Curr. Opin. Pharmacol. 11, 439–445 (2011).

    CAS  PubMed  Google Scholar 

  76. 76

    Olivares, J. 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. Environ. Microbiol. 14, 1968–1981 (2012).

    CAS  PubMed  Google Scholar 

  77. 77

    Sanchez, M. B. & Martinez, J. L. Differential epigenetic compatibility of qnr antibiotic resistance determinants with the chromosome of Escherichia coli. PLoS ONE 7, e35149 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Levin, B. R., Perrot, V. & Walker, N. Compensatory mutations, antibiotic resistance and the population genetics of adaptive evolution in bacteria. Genetics 154, 985–997 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Steinkraus, G., White, R. & Friedrich, L. Vancomycin MIC creep in non-vancomycin-intermediate Staphylococcus aureus (VISA), vancomycin-susceptible clinical methicillin-resistant S. aureus (MRSA) blood isolates from 2001–2005. J. Antimicrob. Chemother. 60, 788–794 (2007).

    CAS  PubMed  Google Scholar 

  80. 80

    Gibson, M. K., Forsberg, K. J. & Dantas, G. Improved annotation of antibiotic resistance determinants reveals microbial resistomes cluster by ecology. ISME J. http://dx.doi.org/10.1038/ismej.2014.106 (2014).

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Research in the author's laboratories is funded by the European Commission (EvoTAR-282004 for JLM, TMC and FB), the Ministry of Economy and Competitiveness (BIO2011-25255 for JLM, PI12-01581 for TMC, PI10-02588 for FB, and NEXTMICRO for FB and TMC), the Regional Government of Madrid in Spain (PROMPT-S2010/BMD2414 for JLM and FB), and by the Spanish Network for Research on Infectious Diseases (REIPI RD12/0015 for JLM) and the Spanish Network for the Study of Plasmids and Extrachromosomal Elements (REDEEX, BFU2011-14145-E for TMC).

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Martínez, J., Coque, T. & Baquero, F. What is a resistance gene? Ranking risk in resistomes. Nat Rev Microbiol 13, 116–123 (2015). https://doi.org/10.1038/nrmicro3399

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