The antibiotic resistome: the nexus of chemical and genetic diversity

Key Points

  • The antibiotic resistome is the collection of all the antibiotic resistance genes, including those usually associated with pathogenic bacteria isolated in the clinics, non-pathogenic antibiotic producing bacteria and all other resistance genes.

  • Many bacterial genomes contain cryptic resistance genes that can confer resistance, but do not seem to have been selected in response to recent exposure to antibiotics. These represent a large reservoir of antibiotic resistance genes.

  • The antibiotic resistance genes in environmental and other non-pathogenic bacteria share amino-acid sequence similarities and biochemical mechanisms with resistance elements in clinical isolates.

  • Structural biology and protein biochemistry has revealed that antibiotic resistance has evolved from precursor proteins with other metabolic functions. The powerful selection pressure produced by the use of cytotoxic antimicrobial agents spurs the selection of resistance mechanisms from these precursors.

  • Antibiotics are ancient, dating back hundreds of millions of years. Resistance is therefore equally ancient, and the number of genes in the resistome is a reflection of the continuous co-evolution of small molecules in natural environments and microbial genomes.

Abstract

Over the millennia, microorganisms have evolved evasion strategies to overcome a myriad of chemical and environmental challenges, including antimicrobial drugs. Even before the first clinical use of antibiotics more than 60 years ago, resistant organisms had been isolated. Moreover, the potential problem of the widespread distribution of antibiotic resistant bacteria was recognized by scientists and healthcare specialists from the initial use of these drugs. Why is resistance inevitable and where does it come from? Understanding the molecular diversity that underlies resistance will inform our use of these drugs and guide efforts to develop new efficacious antibiotics.

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Figure 1: The antibiotic resistome.
Figure 2: Streptogramin antibiotics and streptogramin resistance.
Figure 3: Genome context of chromosomal antibiotic resistance genes.
Figure 4: Vancomycin resistance: an elegant mechanism of antibiotic evasion.
Figure 5: Vancomycin-resistance genes are widespread in the environment.
Figure 6: Evolution of antibiotic resistance proteins.

References

  1. 1

    Winau, F., Westphal, O. & Winau, R. Paul Ehrlich — in search of the magic bullet. Microbes Infect. 6, 786–789 (2004).

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Overbye, K. M. & Barrett, J. F. Antibiotics: where did we go wrong? Drug Discov. Today 10, 45–52 (2005).

    PubMed  Article  Google Scholar 

  3. 3

    Projan, S. J. Why is big Pharma getting out of antibacterial drug discovery? Curr. Opin. Microbiol. 6, 427–430 (2003). An excellent discussion of the challenges of modern antimicrobial drug discovery.

    PubMed  PubMed Central  Article  Google Scholar 

  4. 4

    Projan, S. J. & Shlaes, D. M. Antibacterial drug discovery: is it all downhill from here? Clin. Microbiol. Infect. 10 (Suppl. 4), 18–22 (2004).

    PubMed  Article  Google Scholar 

  5. 5

    Tenover, F. C. Mechanisms of antimicrobial resistance in bacteria. Am. J. Med. 119, S3–S10; discussion S62–S70 (2006).

    CAS  PubMed  Article  Google Scholar 

  6. 6

    McGowan, J. E. Jr . Resistance in nonfermenting Gram-negative bacteria: multidrug resistance to the maximum. Am. J. Infect. Control 34, S29–S37; discussion S64–S73 (2006).

    PubMed  Article  Google Scholar 

  7. 7

    Giamarellos-Bourboulis, E. J. et al. Clarithromycin is an effective immunomodulator in experimental pyelonephritis caused by pan-resistant Klebsiella pneumoniae. J. Antimicrob. Chemother. 57, 937–944 (2006).

    CAS  PubMed  Article  Google Scholar 

  8. 8

    Levy, S. B. & Marshall, B. Antibacterial resistance worldwide: causes, challenges and responses. Nature Med. 10, S122–S129 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9

    Livermore, D. M. The need for new antibiotics. Clin. Microbiol. Infect. 10 (Suppl. 4), 1–9 (2004).

    PubMed  Article  Google Scholar 

  10. 10

    Alekshun, M. N. & Levy, S. B. Commensals upon us. Biochem. Pharmacol. 71, 893–900 (2006).

    CAS  PubMed  Article  Google Scholar 

  11. 11

    Rice, L. B. Unmet medical needs in antibacterial therapy. Biochem. Pharmacol. 71, 991–995 (2006).

    CAS  PubMed  Article  Google Scholar 

  12. 12

    Robinson, D. A. et al. Re-emergence of early pandemic Staphylococcus aureus as a community-acquired methicillin-resistant clone. Lancet 365, 1256–1258 (2005).

    PubMed  Article  Google Scholar 

  13. 13

    File, T. M. Jr . Clinical implications and treatment of multiresistant Streptococcus pneumoniae pneumonia. Clin. Microbiol. Infect. 12 (Suppl. 3), 31–41 (2006).

    CAS  PubMed  Article  Google Scholar 

  14. 14

    Nguyen, L. & Thompson, C. J. Foundations of antibiotic resistance in bacterial physiology: the mycobacterial paradigm. Trends Microbiol. 14, 304–312 (2006).

    CAS  PubMed  Article  Google Scholar 

  15. 15

    Riley, M. et al. Escherichia coli K-12: a cooperatively developed annotation snapshot — 2005. Nucleic Acids Res. 34, 1–9 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16

    Yu, E. W., McDermott, G., Zgurskaya, H. I., Nikaido, H. & Koshland, D. E. Jr . Structural basis of multiple drug-binding capacity of the AcrB multidrug efflux pump. Science 300, 976–980 (2003).

    CAS  PubMed  Article  Google Scholar 

  17. 17

    Hillen, W. & Berens, C. Mechanisms underlying expression of Tn10 encoded tetracycline resistance. Annu. Rev. Microbiol. 48, 345–369 (1994).

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Ramos, J. L. et al. The TetR family of transcriptional repressors. Microbiol. Mol. Biol. Rev. 69, 326–356 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19

    Alekshun, M. N. & Levy, S. B. The mar regulon: multiple resistance to antibiotics and other toxic chemicals. Trends Microbiol. 7, 410–413 (1999).

    CAS  PubMed  Article  Google Scholar 

  20. 20

    Tsui, W. H. et al. Dual effects of MLS antibiotics: transcriptional modulation and interactions on the ribosome. Chem. Biol. 11, 1307–1316 (2004).

    CAS  PubMed  Article  Google Scholar 

  21. 21

    Goh, E. B. et al. Transcriptional modulation of bacterial gene expression by subinhibitory concentrations of antibiotics. Proc. Natl Acad. Sci. USA 99, 17025–17030 (2002).

    CAS  PubMed  Article  Google Scholar 

  22. 22

    Wright, G. D. Bacterial resistance to antibiotics: enzymatic degradation and modification. Adv. Drug Deliv. Rev. 57, 1451–1470 (2005).

    CAS  PubMed  Article  Google Scholar 

  23. 23

    Pootoolal, J., Neu, J. & Wright, G. D. Glycopeptide antibiotic resistance. Annu. Rev. Pharmacol. Toxicol. 42, 381–408 (2002).

    CAS  PubMed  Article  Google Scholar 

  24. 24

    Walsh, C. T., Fisher, S. L., Park, I.-S., Prohalad, M. & Wu, Z. Bacterial resistance to vancomycin: five genes and one missing hydrogen bond tell the story. Chem. Biol. 3, 21–28 (1996).

    CAS  PubMed  Article  Google Scholar 

  25. 25

    Wilson, P. et al. Linezolid resistance in clinical isolates of Staphylococcus aureus. J. Antimicrob. Chemother. 51, 186–188 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26

    Poole, K. Aminoglycoside resistance in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 49, 479–487 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27

    D'Costa, V. M., McGrann, K. M., Hughes, D. W. & Wright, G. D. Sampling the antibiotic resistome. Science 311, 374–377 (2006). This manuscript describes a systematic study of the level of antibiotic resistance in a population of environmental bacteria that demonstrates that multidrug resistance is much more prevalent than previously thought.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28

    Piddock, L. J. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin. Microbiol. Rev. 19, 382–402 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29

    Poole, K. & Srikumar, R. Multidrug efflux in Pseudomonas aeruginosa: components, mechanisms and clinical significance. Curr. Top Med. Chem. 1, 59–71 (2001).

    CAS  PubMed  Article  Google Scholar 

  30. 30

    Stover, C. K. et al. Complete genome sequence of Pseudomonas aeruginosa PA01, an opportunistic pathogen. Nature 406, 959–964 (2000).

    CAS  Article  Google Scholar 

  31. 31

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

    CAS  Article  Google Scholar 

  32. 32

    Fisher, J. F., Meroueh, S. O. & Mobashery, S. Bacterial resistance to β-lactam antibiotics: compelling opportunism, compelling opportunity. Chem. Rev. 105, 395–424 (2005).

    CAS  PubMed  Article  Google Scholar 

  33. 33

    Sugantino, M. & Roderick, S. L. Crystal structure of Vat(D): an acetyltransferase that inactivates streptogramin group A antibiotics. Biochemistry 41, 2209–2216 (2002).

    CAS  PubMed  Article  Google Scholar 

  34. 34

    Seoane, A. & Garcia Lobo, J. M. Identification of a streptogramin A acetyltransferase gene in the chromosome of Yersinia enterocolitica. Antimicrob. Agents Chemother. 44, 905–909 (2000). A study that shows that type A streptogramin acetyltransferases are widely distributed in bacterial genomes.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35

    Mukhtar, T. A., Koteva, K. P., Hughes, D. W. & Wright, G. D. Vgb from Staphylococcus aureus inactivates streptogramin B antibiotics by an elimination mechanism not hydrolysis. Biochemistry 40, 8877–8886 (2001).

    CAS  PubMed  Article  Google Scholar 

  36. 36

    Canton, R. & Coque, T. M. The CTX-M b-lactamase pandemic. Curr. Opin. Microbiol. 9, 466–475 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37

    Humeniuk, C. et al. β-Lactamases of Kluyvera ascorbata, probable progenitors of some plasmid-encoded CTX-M types. Antimicrob. Agents Chemother. 46, 3045–3049 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38

    Poirel, L., Kampfer, P. & Nordmann, P. Chromosome-encoded Ambler class A β-lactamase of Kluyvera georgiana, a probable progenitor of a subgroup of CTX-M extended-spectrum β-lactamases. Antimicrob. Agents Chemother. 46, 4038–4040 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39

    Decousser, J. W., Poirel, L. & Nordmann, P. Characterization of a chromosomally encoded extended-spectrum class A β-lactamase from Kluyvera cryocrescens. Antimicrob. Agents Chemother. 45, 3595–3598 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40

    Lartigue, M. F., Poirel, L., Aubert, D. & Nordmann, P. In vitro analysis of ISEcp1B-mediated mobilization of naturally occurring β-lactamase gene blaCTX-M of Kluyvera ascorbata. Antimicrob. Agents Chemother. 50, 1282–1286 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41

    Wright, G. D., Berghuis, A. M. & Mobashery, S. Aminoglycoside antibiotics. Structures, functions, and resistance. Adv. Exp. Med. Biol. 456, 27–69 (1998).

    CAS  PubMed  Article  Google Scholar 

  42. 42

    Hachler, H., Santarnam, P. & Kayser, F. H. Sequence and characterization of a novel chromosomal aminoglycoside phosphotransferase gene aph(3')-IIb in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 40, 1254–1256 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43

    Thompson, P. R., Hughes, D. W., Cianciotto, N. P. & Wright, G. D. Spectinomycin kinase from Legionella pneumophila, Characterization of substrate specificity and identification of catalytically important residues. J. Biol. Chem. 273, 14788–14795 (1998).

    CAS  PubMed  Article  Google Scholar 

  44. 44

    Draker, K. A., Boehr, D. D., Elowe, N. H., Noga, T. J. & Wright, G. D. Functional annotation of putative aminoglycoside antibiotic modifying proteins in Mycobacterium tuberculosis H37Rv. J. Antibiot. (Tokyo) 56, 135–142 (2003).

    CAS  Article  Google Scholar 

  45. 45

    Poirel, L., Decousser, J. W. & Nordmann, P. Insertion sequence ISEcp1B is involved in expression and mobilization of a bla(CTX-M) β-lactamase gene. Antimicrob. Agents Chemother. 47, 2938–2945 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46

    Toleman, M. A., Bennett, P. M. & Walsh, T. R. ISCR elements: novel gene-capturing systems of the 21st century? Microbiol. Mol. Biol. Rev. 70, 296–316 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47

    Hall, R. M. & Collis, C. M. Antibiotic resistance in Gram-negative bacteria: the role of gene cassettes and integrons. Drug Resist. Updat. 1, 109–119 (1998).

    CAS  PubMed  Article  Google Scholar 

  48. 48

    Finan, T. M. et al. The complete sequence of the 1,683-kb pSymB megaplasmid from the N2-fixing endosymbiont Sinorhizobium meliloti. Proc. Natl Acad. Sci. USA 98, 9889–9894 (2001).

    CAS  PubMed  Article  Google Scholar 

  49. 49

    Gilmour, M. W., Thomson, N. R., Sanders, M., Parkhill, J. & Taylor, D. E. The complete nucleotide sequence of the resistance plasmid R478: defining the backbone components of incompatibility group H conjugative plasmids through comparative genomics. Plasmid 52, 182–202 (2004).

    CAS  PubMed  Article  Google Scholar 

  50. 50

    O'Driscoll, J., Glynn, F., Fitzgerald, G. F. & van Sinderen, D. Sequence analysis of the lactococcal plasmid pNP40: a mobile replicon for coping with environmental hazards. J. Bacteriol. 188, 6629–6639 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51

    Baltz, R. H. Antibiotic discovery from actinomycetes: will a renaissance follow the decline and fall? SIM News 55, 186–196 (2005). An estimate of the age of antibiotic biosynthesis clusters in antibiotic-producing bacteria.

    Google Scholar 

  52. 52

    Hall, B. G. & Barlow, M. Evolution of the serine β-lactamases: past, present and future. Drug Resist. Updat. 7, 111–123 (2004).

    CAS  PubMed  Article  Google Scholar 

  53. 53

    Cundliffe, E. How antibiotic-producing organisms avoid suicide. Annu. Rev. Microbiol. 43, 207–233 (1989).

    CAS  Article  Google Scholar 

  54. 54

    Barna, J. C. & Williams, D. H. The structure and mode of action of glycopeptide antibiotics of the vancomycin group. Annu. Rev. Microbiol. 38, 339–357 (1984).

    CAS  PubMed  Article  Google Scholar 

  55. 55

    Kirst, H. A., Thompson, D. G. & Nicas, T. I. Historical yearly usage of vancomycin. Antimicrob. Agents Chemother. 42, 1303–1304 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56

    Leclercq, R., Derlot, E., Duval, J. & Courvalin, P. Plasmid-mediated resistance to vancomycin and teicoplanin in Enterococcus faecium. N. Engl. J. Med. 319, 157–161 (1988).

    CAS  PubMed  Article  Google Scholar 

  57. 57

    Tenover, F. C. et al. Vancomycin-resistant Staphylococcus aureus isolate from a patient in Pennsylvania. Antimicrob. Agents Chemother. 48, 275–280 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58

    Whitener, C. J. et al. Vancomycin-resistant Staphylococcus aureus in the absence of vancomycin exposure. Clin. Infect Dis. 38, 1049–1055 (2004).

    PubMed  Article  Google Scholar 

  59. 59

    Arthur, M. et al. Mechanisms of glycopeptide resistance in enterococci. J. Infect. 32, 11–16 (1996).

    CAS  PubMed  Article  Google Scholar 

  60. 60

    Courvalin, P. Vancomycin resistance in Gram-positive cocci. Clin. Infect Dis. 42 (Suppl. 1), 25–34 (2006).

    Article  Google Scholar 

  61. 61

    Bugg, T. D. H. et al. Molecular basis for vancomycin resistance in Enterococcus faecium BM4147: biosynthesis of a depsipeptide peptidoglycan precursor by vancomycin resistance proteins VanH and VanA. Biochemistry 30, 10408–10415 (1991).

    CAS  PubMed  Article  Google Scholar 

  62. 62

    Marshall, C. G., Broadhead, G., Leskiw, B. K. & Wright, G. D. D-ala-D-ala ligases from glycopeptide antibiotic-producing organisms are highly homologous to the enterococcal vancomycin-resistance ligases VanA and VanB. Proc. Natl Acad. Sci. USA 94, 6480–6483 (1997).

    CAS  PubMed  Article  Google Scholar 

  63. 63

    Marshall, C. G., Lessard, I. A., Park, I. & Wright, G. D. Glycopeptide antibiotic resistance genes in glycopeptide-producing organisms. Antimicrob. Agents Chemother. 42, 2215–2220 (1998). Study that shows that non-pathogenic glycopeptide antibiotic producers share the same resistance enzymes that are found in vancomycin clinical isolates.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64

    Marshall, C. G. & Wright, G. D. The glycopeptide antibiotic producer Streptomyces toyocaensis NRRL 15009 has both D-alanyl-D-alanine and D-alanyl-D-lactate ligases. FEMS Microbiol. Lett. 157, 295–299 (1997).

    CAS  PubMed  Article  Google Scholar 

  65. 65

    Marshall, C. G. & Wright, G. D. DdlN from vancomycin-producing Amycolatopsis orientalis C329.2 is a VanA homologue with D-alanyl-D-lactate ligase activity. J. Bacteriol. 180, 5792–5795 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Marshall, C. G., Zolli, M. & Wright, G. D. Molecular mechanism of VanHst, an α-ketoacid dehydrogenase required for glycopeptide antibiotic resistance from a glycopeptide producing organism. Biochemistry 38, 8485–8491 (1999).

    CAS  PubMed  Article  Google Scholar 

  67. 67

    Hong, H. J. et al. Characterization of an inducible vancomycin resistance system in Streptomyces coelicolor reveals a novel gene (vanK) required for drug resistance. Mol. Microbiol. 52, 1107–1121 (2004).

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Patel, R., Piper, K., Cockerill, F. R., Steckelberg, J. M. & Yousten, A. A. The biopesticide Paenibacillus popilliae has a vancomycin resistance gene cluster homologous to the enterococcal VanA vancomycin resistance gene cluster. Antimicrob. Agents Chemother. 44, 705–709 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69

    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). First study to show the similarity of antibiotic resistance mechanisms in pathogenic bacteria and antibiotic producers.

    CAS  Article  Google Scholar 

  70. 70

    Piepersberg, W. in Biotechnology of industrial antibiotics (ed. Strohl, W.) 81–163 (Marcel Dekker, New York, 1997).

    Google Scholar 

  71. 71

    Boehr, D. D., Thompson, P. R. & Wright, G. D. Molecular mechanism of aminoglycoside antibiotic kinase APH(3′)-IIIa: roles of conserved active site residues. J. Biol. Chem. 276, 23929–23936 (2001).

    CAS  PubMed  Article  Google Scholar 

  72. 72

    Daigle, D. M., McKay, G. A., Thompson, P. R. & Wright, G. D. Aminoglycoside phosphotransferases required for antibiotic resistance are also serine protein kinases. Chem. Biol. 6, 11–18 (1998).

    Article  Google Scholar 

  73. 73

    Daigle, D. M., McKay, G. A. & Wright, G. D. Inhibition of aminoglycoside antibiotic resistance enzymes by protein kinase inhibitors. J. Biol. Chem. 272, 24755–24758 (1997).

    CAS  PubMed  Article  Google Scholar 

  74. 74

    Hon, W. C. et al. Structure of an enzyme required for aminoglycoside resistance reveals homology to eukaryotic protein kinases. Cell 89, 887–895 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75

    Deutscher, J. & Saier, M. H. Jr. Ser/Thr/Tyr protein phosphorylation in bacteria — for long time neglected, now well established. J. Mol. Microbiol. Biotechnol. 9, 125–131 (2005).

    CAS  PubMed  Article  Google Scholar 

  76. 76

    Kennelly, P. J. & Potts, M. Fancy meeting you here! a fresh look at 'prokaryotic' protein phosphorylation. J. Bacteriol. 178, 4759–4764 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77

    Bentley, S. D. et al. Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417, 141–147 (2002).

    Article  Google Scholar 

  78. 78

    Ikeda, H. et al. Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis. Nature Biotechnol. 21, 526–531 (2003).

    Article  Google Scholar 

  79. 79

    Vetting, M. W., Hegde, S. S., Javid-Majd, F., Blanchard, J. S. & Roderick, S. L. Aminoglycoside 2′-N-acetyltransferase from Mycobacterium tuberculosis in complex with coenzyme A and aminoglycoside substrates. Nature Struct. Biol. 9, 653–658 (2002).

    CAS  PubMed  Article  Google Scholar 

  80. 80

    Vetting, M. W., Magnet, S., Nieves, E., Roderick, S. L. & Blanchard, J. S. A bacterial acetyltransferase capable of regioselective N-acetylation of antibiotics and histones. Chem. Biol. 11, 565–573 (2004).

    CAS  PubMed  Article  Google Scholar 

  81. 81

    Wolf, E. et al. Crystal structure of a GCN5-related N-acetyltransferase: Serratia marcescens aminoglycoside 3-N-acetyltransferase. Cell 94, 439–449 (1998).

    CAS  PubMed  Article  Google Scholar 

  82. 82

    Wybenga-Groot, L., Draker, K. a., Wright, G. D. & Berghuis, A. M. Crystal structure of an aminoglycoside 6′-N-acetyltransferase:defining the GCN5-related N-acetyltransferase superfamily fold. Structure 7, 497–507 (1999).

    CAS  PubMed  Article  Google Scholar 

  83. 83

    Vetting, M. W. et al. Structure and functions of the GNAT superfamily of acetyltransferases. Arch. Biochem. Biophys. 433, 212–226 (2005).

    CAS  PubMed  Article  Google Scholar 

  84. 84

    Massova, I. & Mobashery, S. Kinship and diversification of bacterial penicillin-binding proteins and b-lactamases. Antimicrob. Agents Chemother. 42, 1–17 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85

    Robicsek, A. et al. Fluoroquinolone-modifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase. Nature Med. 12, 83–88 (2006). Remarkable description of the evolution of an aminoglycoside resistance enzyme into a form that can modify the fluoroquinolone antibiotic ciprofloxacin resulting in resistance.

    CAS  PubMed  Article  Google Scholar 

  86. 86

    Cirz, R. T. et al. Inhibition of mutation and combating the evolution of antibiotic resistance. PLoS Biol. 3, e176 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  87. 87

    Cirz, R. T., O' Neill B, M., Hammond, J. A., Head, S. R. & Romesberg, F. E. Defining the Pseudomonas aeruginosa SOS response and its role in the global response to the antibiotic ciprofloxacin. J. Bacteriol. 188, 7101–7110 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88

    Heinemann, J. A. How antibiotics cause antibiotic resistance. Drug Discov. Today 4, 72–79 (1999).

    CAS  PubMed  Article  Google Scholar 

  89. 89

    Morris, R. P. et al. Ancestral antibiotic resistance in Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 102, 12200–12205 (2005).

    CAS  PubMed  Article  Google Scholar 

  90. 90

    Walsh, C. T. Polyketide and nonribosomal peptide antibiotics: modularity and versatility. Science 303, 1805–1810 (2004).

    CAS  PubMed  Article  Google Scholar 

  91. 91

    Yim, G., Wang, H. H. & Davies, J. The truth about antibiotics. Int. J. Med. Microbiol. 296, 163–170 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92

    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). First report of antibiotic resistance genes in the soil bacterial metagenome.

    CAS  Article  Google Scholar 

  93. 93

    Yeh, P., Tschumi, A. I. & Kishony, R. Functional classification of drugs by properties of their pairwise interactions. Nature Genet. 38, 489–494 (2006).

    CAS  PubMed  Article  Google Scholar 

  94. 94

    Andersson, D. I. The biological cost of mutational antibiotic resistance: any practical conclusions? Curr. Opin. Microbiol. 9, 461–465 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95

    Andersson, D. I. Persistence of antibiotic resistant bacteria. Curr. Opin. Microbiol. 6, 452–456 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96

    Handel, A., Regoes, R. R. & Antia, R. The role of compensatory mutations in the emergence of drug resistance. PLoS Comput. Biol. 2, e137 (2006).

    PubMed  PubMed Central  Article  Google Scholar 

  97. 97

    Kim, C., Cha, J. Y., Yan, H., Vakulenko, S. B. & Mobashery, S. Hydrolysis of ATP by aminoglycoside 3′-phosphotransferases: an unexpected cost to bacteria for harboring an antibiotic resistance enzyme. J. Biol. Chem. 281, 6964–6969 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98

    Thompson, J. D., Higgins, D. G. & Gibson, T. J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 22, 4673–4680 (1994).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99

    Perrière, G. & Gouy, M. WWW-Query: an on-line retrieval system for biological sequence banks. Biochimie 78, 364–369 (1996).

    PubMed  Article  Google Scholar 

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Acknowledgements

The author's research in antibiotic resistance is supported by the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada and a Canada Research Chair in Antibiotic Biochemistry.

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DATABASES

Entrez Genome Project

Acinetobacter baumannii

Bordetella pertussis

Burkholderia cepacia

Escherichia coli

Klebsiella pneumoniae

Legionella pneumophila

Mycobacterium smegmatis

Mycobacterium tuberculosis

Pseudomonas aeruginosa

Salmonella enterica serovar Typhimurium

Staphylococcus aureus

Stenotrophomonas maltophilia

Streptococcus pneumoniae

Streptomyces avermitilis

Streptomyces coelicolor

Yersinia enterocolitica

FURTHER INFORMATION

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Glossary

Superbug

A bacterial pathogen that is resistant to multiple antibiotics.

Resistome

A collection of all the antibiotic resistance genes and their precursors in pathogenic and non-pathogenic bacteria.

Cryptic resistance gene

A resistance gene that is embedded in a bacterial chromosome, but that is not obviously associated with antibiotic resistance. Usually either not expressed, or expressed at low levels.

R-plasmid

A plasmid that is present in bacterial pathogens and environmental microorganisms, and that contains one or more antibiotic resistance genes.

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Wright, G. The antibiotic resistome: the nexus of chemical and genetic diversity. Nat Rev Microbiol 5, 175–186 (2007). https://doi.org/10.1038/nrmicro1614

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