Advertisement

The Origins of Antibiotic Resistance

  • Gerard D. Wright
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 211)

Abstract

Antibiotics remain one of our most important pharmacological tools for the control of infectious disease. However, unlike most other drugs, the use of antibiotics selects for resistant organisms and erodes their clinical utility. Resistance can emerge within populations of bacteria by mutation and be retained by subsequent selection or by the acquisition of resistance elements laterally from other organisms. The source of these resistance genes is only now being understood. The evidence supports a large bacterial resistome—the collection of all resistance genes and their precursors in both pathogenic and nonpathogenic bacteria. These genes have arisen by various means including self-protection in the case of antibiotic producers, transport of small molecules for various reasons including nutrition and detoxification of noxious chemicals, and to accomplish other goals, such as metabolism, and demonstrate serendipitous selectivity for antibiotics. Regardless of their origins, resistance genes can rapidly move through bacterial populations and emerge in pathogenic bacteria. Understanding the processes that contribute to the evolution and selection of resistance is essential to mange current stocks of antibiotics and develop new ones.

Keywords

Resistome Efflux Evolution Lateral gene transfer 

Notes

Acknowledgements

Research in the author’s lab on antibiotic resistance is supported by a Canada Research Chair, the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada.

References

  1. Abraham EP, Chain E (1940) An enzyme from bacteria able to destroy penicillin. Nature 146:837CrossRefGoogle Scholar
  2. Allen HK, Moe LA et al (2009) Functional metagenomics reveals diverse beta-lactamases in a remote Alaskan soil. ISME J 3(2):243–51PubMedCrossRefGoogle Scholar
  3. Allwood AC, Walter MR et al (2006) Stromatolite reef from the Early Archaean era of Australia. Nature 441(7094):714–8PubMedCrossRefGoogle Scholar
  4. Alvarez-Ortega C, Wiegand I et al (2010) Genetic determinants involved in the susceptibility of Pseudomonas aeruginosa to beta-lactam antibiotics. Antimicrob Agents Chemother 54(10):4159–67PubMedCrossRefGoogle Scholar
  5. Andersson DI (2006) The biological cost of mutational antibiotic resistance: any practical conclusions? Curr Opin Microbiol 9(5):461–5PubMedCrossRefGoogle Scholar
  6. Andersson DI, Hughes D (2010) Antibiotic resistance and its cost: is it possible to reverse resistance? Nat Rev Microbiol 8(4):260–71PubMedGoogle Scholar
  7. Baba T, Ara T et al (2006) Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol Syst Biol 2:0008PubMedCrossRefGoogle Scholar
  8. Bailey AM, Ivens A et al (2010) RamA, a member of the AraC/XylS family, influences both virulence and efflux in Salmonella enterica serovar Typhimurium. J Bacteriol 192(6):1607–16PubMedCrossRefGoogle Scholar
  9. Barlow M (2009) What antimicrobial resistance has taught us about horizontal gene transfer. Methods Mol Biol 532:397–411PubMedCrossRefGoogle Scholar
  10. Benveniste R, Davies J (1973) Aminoglycoside antibiotic-inactivating enzymes in actinomycetes similar to those present in clinical isolates of antibiotic-resistant bacteria. Proc Natl Acad Sci USA 70:2276–2280PubMedCrossRefGoogle Scholar
  11. Bergthorsson U, Andersson DI et al (2007) Ohno’s dilemma: evolution of new genes under continuous selection. Proc Natl Acad Sci USA 104(43):17004–9PubMedCrossRefGoogle Scholar
  12. Boucher HW, Talbot GH et al (2009) Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 48(1):1–12PubMedCrossRefGoogle Scholar
  13. Breidenstein EB, Khaira BK et al (2008) Complex ciprofloxacin resistome revealed by screening a Pseudomonas aeruginosa mutant library for altered susceptibility. Antimicrob Agents Chemother 52(12):4486–91PubMedCrossRefGoogle Scholar
  14. Bugg TDH, Wright GD et al (1991) Molecular basis for vancomycin resistance in Enterococcus faecium BM4147: biosynthesis of a depsipeptide peptidoglycan precursor by vancomycin resistance proteins VanH and VanA. Biochemistry 30:10408–10415PubMedCrossRefGoogle Scholar
  15. Canton R, Coque TM (2006) The CTX-M beta-lactamase pandemic. Curr Opin Microbiol 9(5):466–75PubMedCrossRefGoogle Scholar
  16. Cirz RT, O’Neill BM et al (2006) Defining the Pseudomonas aeruginosa SOS Response and Its Role in the Global Response to the Antibiotic Ciprofloxacin. J Bacteriol 188(20):7101–10PubMedCrossRefGoogle Scholar
  17. Courvalin P (2006) Vancomycin resistance in gram-positive cocci. Clin Infect Dis 42(Suppl 1):S25–34PubMedCrossRefGoogle Scholar
  18. Croucher NJ, Walker D et al (2009) Role of conjugative elements in the evolution of the multidrug-resistant pandemic clone Streptococcus pneumoniaeSpain23F ST81. J Bacteriol 191(5):1480–9PubMedCrossRefGoogle Scholar
  19. Cundliffe E (1989) How antibiotic-producing organisms avoid suicide. Annu Rev Microbiol 43:207–33PubMedCrossRefGoogle Scholar
  20. Cundliffe E, Bate N et al (2001) The tylosin-biosynthetic genes of Streptomyces fradiae. Antonie Van Leeuwenhoek 79(3–4):229–34PubMedCrossRefGoogle Scholar
  21. Daigle DM, McKay GA et al (1997) Inhibition of aminoglycoside antibiotic resistance enzymes by protein kinase inhibitors. J Biol Chem 272:24755–24758PubMedCrossRefGoogle Scholar
  22. Daigle DM, McKay GA et al (1998) Aminoglycoside phosphotransferases required for antibiotic resistance are also Serine protein kinases. Chem Biol 6:11–18CrossRefGoogle Scholar
  23. Dantas G, Sommer MO et al (2008) Bacteria subsisting on antibiotics. Science 320(5872):100–3PubMedCrossRefGoogle Scholar
  24. Davies J (1995) Vicious circles: looking back on resistance plasmids. Genetics 139(4):1465–8PubMedGoogle Scholar
  25. D’Costa VM, McGrann KM et al (2006) Sampling the antibiotic resistome. Science 311(5759):374–7PubMedCrossRefGoogle Scholar
  26. D’Costa VM, Griffiths E et al (2007) Expanding the soil antibiotic resistome: exploring environmental diversity. Curr Opin Microbiol 10(5):481–9PubMedCrossRefGoogle Scholar
  27. De Pascale G, Wright GD (2010) Antibiotic resistance by enzyme inactivation: from mechanisms to solutions. Chembiochem 11(10):1325–34PubMedCrossRefGoogle Scholar
  28. Decousser JW, Poirel L et al (2001) Characterization of a chromosomally encoded extended-spectrum class A beta-lactamase from Kluyvera cryocrescens. Antimicrob Agents Chemother 45(12):3595–8PubMedCrossRefGoogle Scholar
  29. Donato JJ, Moe LA et al (2010) Metagenomics reveals antibiotic resistance genes encoding predicted bifunctional proteins in apple orchard soil. Appl Environ Microbiol 76:4396–4401PubMedCrossRefGoogle Scholar
  30. Dwyer DJ, Kohanski MA et al (2007) Gyrase inhibitors induce an oxidative damage cellular death pathway in Escherichia coli. Mol Syst Biol 3:91PubMedCrossRefGoogle Scholar
  31. Fajardo A, Martinez-Martin N et al (2008) The neglected intrinsic resistome of bacterial pathogens. PLoS One 3(2):e1619PubMedCrossRefGoogle Scholar
  32. Fischbach MA, Walsh CT (2009) Antibiotics for emerging pathogens. Science 325(5944):1089–93PubMedCrossRefGoogle Scholar
  33. Folster JP, Johnson PJ et al (2009) MtrR modulates rpoH expression and levels of antimicrobial resistance in Neisseria gonorrhoeae. J Bacteriol 191(1):287–97PubMedCrossRefGoogle Scholar
  34. Fong DH, Lemke CT et al (2010) Structure of the antibiotic resistance factor spectinomycin phosphotransferase from Legionella pheumophila. J Biol Chem 285(13):9545–55PubMedCrossRefGoogle Scholar
  35. Freitas AR, Tedim AP et al (2010) Global spread of the hyl(Efm) colonization-virulence gene in megaplasmids of the Enterococcus faecium CC17 polyclonal subcluster. Antimicrob Agents Chemother 54(6):2660–5PubMedCrossRefGoogle Scholar
  36. Guardabassi L, Agerso Y (2006) Genes homologous to glycopeptide resistance vanA are widespread in soil microbial communities. FEMS Microbiol Lett 259(2):221–5PubMedCrossRefGoogle Scholar
  37. Guardabassi L, Perichon B et al (2005) Glycopeptide resistance vanA operons in Paenibacillus strains isolated from soil. Antimicrob Agents Chemother 49(10):4227–33PubMedCrossRefGoogle Scholar
  38. Gwynn MN, Portnoy A et al (2010) Challenges of antibacterial discovery revisited. Ann N Y Acad Sci 1213:5–19PubMedCrossRefGoogle Scholar
  39. Hon WC, McKay GA et al (1997) Structure of an enzyme required for aminoglycoside antibiotic resistance reveals homology to eukaryotic protein kinases. Cell 89(6):887–95PubMedCrossRefGoogle Scholar
  40. Hong HJ, Hutchings MI et al (2004) Characterization of an inducible vancomycin resistance system in Streptomyces coelicolor reveals a novel gene (vanK) required for drug resistance. Mol Microbiol 52(4):1107–21PubMedCrossRefGoogle Scholar
  41. Hooper DC (1999) Mechanisms of fluoroquinolone resistance. Drug Resist Updat 2(1):38–55PubMedCrossRefGoogle Scholar
  42. Hooper DC (2001) Mechanisms of action of antimicrobials: focus on fluoroquinolones. Clin Infect Dis 32(Suppl 1):S9–S15PubMedCrossRefGoogle Scholar
  43. Humeniuk C, Arlet G et al (2002) Beta-lactamases of Kluyvera ascorbata, probable progenitors of some plasmid-encoded CTX-M types. Antimicrob Agents Chemother 46(9):3045–9PubMedCrossRefGoogle Scholar
  44. Infectious Diseases Society of America (2010) The 10 × ‘20 Initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clin Infect Dis 50(8):1081–3CrossRefGoogle Scholar
  45. Karray F, Darbon E et al (2007) Organization of the biosynthetic gene cluster for the macrolide antibiotic spiramycin in Streptomyces ambofaciens. Microbiology 153(Pt 12):4111–22PubMedCrossRefGoogle Scholar
  46. Kaufmann BB, Hung DT (2010) The fast track to multidrug resistance. Mol Cell 37(3):297–8PubMedCrossRefGoogle Scholar
  47. Kelly JA, Dideberg O et al (1986) On the origin of bacterial resistance to penicillin: comparison of a beta-lactamase and a penicillin target. Science 231(4744):1429–31PubMedCrossRefGoogle Scholar
  48. Kohanski MA, DePristo MA et al (2010) Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis. Mol Cell 37(3):311–20PubMedCrossRefGoogle Scholar
  49. Koteva K, Hong HJ et al (2010) A vancomycin photoprobe identifies the histidine kinase VanSsc as a vancomycin receptor. Nat Chem Biol 6(5):327–9PubMedCrossRefGoogle Scholar
  50. Lang KS, Anderson JM et al (2010) Novel florfenicol and chloramphenicol resistance gene discovered in Alaskan soil using functional metagenomics. Appl Environ Microbiol 76:5321–5326PubMedCrossRefGoogle Scholar
  51. Laponogov I, Pan XS et al (2010) Structural basis of gate-DNA breakage and resealing by type II topoisomerases. PLoS One 5(6):e11338PubMedCrossRefGoogle Scholar
  52. Leclercq R, Derlot E et al (1988) Plasmid-mediated resistance to vancomycin and teicoplanin in Enterococcus faecium. N Engl J Med 319(3):157–61PubMedCrossRefGoogle Scholar
  53. Liu A, Tran L et al (2010) Antibiotic sensitivity profiles determined with an Escherichia coli gene knockout collection: generating an antibiotic bar code. Antimicrob Agents Chemother 54(4):1393–403PubMedCrossRefGoogle Scholar
  54. Maravic G (2004) Macrolide resistance based on the Erm-mediated rRNA methylation. Curr Drug Targets Infect Disord 4(3):193–202PubMedCrossRefGoogle Scholar
  55. Marshall CG, Lessard IA et al (1998) Glycopeptide antibiotic resistance genes in glycopeptide-producing organisms. Antimicrob Agents Chemother 42(9):2215–20PubMedGoogle Scholar
  56. Massova I, Mobashery S (1998) Kinship and diversification of bacterial penicillin-binding proteins and beta-lactamases. Antimicrob Agents Chemother 42(1):1–17PubMedCrossRefGoogle Scholar
  57. Maveyraud L, Mourey L et al (1998) Structural basis for the clinical longevity of carbapenem antibiotics in the face of challenge by the common A beta-lactamasees from the antibiotic-resistnat bacteria. J Am Chem Soc 120:9748–9752CrossRefGoogle Scholar
  58. Morar M, Wright GD (2010) The genomic enzymology of antibiotic resistance. Annu Rev Genet 44:25–51PubMedCrossRefGoogle Scholar
  59. Morar M, Bhullar K et al (2009) Structure and mechanism of the lincosamide antibiotic adenylyltransferase LinB. Structure 17(12):1649–59PubMedCrossRefGoogle Scholar
  60. Mukhtar TA, Wright GD (2005) Streptogramins, oxazolidinones, and other inhibitors of bacterial protein synthesis. Chem Rev 105(2):529–42PubMedCrossRefGoogle Scholar
  61. Mwangi MM, Wu SW et al (2007) Tracking the in vivo evolution of multidrug resistance in Staphylococcus aureus by whole-genome sequencing. Proc Natl Acad Sci USA 104(22):9451–6PubMedCrossRefGoogle Scholar
  62. Nurizzo D, Shewry SC et al (2003) The crystal structure of aminoglycoside-3'-phosphotransferase-IIa, an enzyme responsible for antibiotic resistance. J Mol Biol 327(2):491–506PubMedCrossRefGoogle Scholar
  63. Oliynyk M, Samborskyy M et al (2007) Complete genome sequence of the erythromycin-producing bacterium Saccharopolyspora erythraea NRRL23338. Nat Biotechnol 25(4):447–453PubMedCrossRefGoogle Scholar
  64. Olson AB, Silverman M et al (2005) Identification of a progenitor of the CTX-M-9 group of extended-spectrum beta-lactamases from Kluyvera georgiana isolated in Guyana. Antimicrob Agents Chemother 49(5):2112–5PubMedCrossRefGoogle Scholar
  65. Peirano G, Pitout JD (2010) Molecular epidemiology of Escherichia coli producing CTX-M beta-lactamases: the worldwide emergence of clone ST131 O25:H4. Int J Antimicrob Agents 35(4):316–21PubMedCrossRefGoogle Scholar
  66. Piddock LJ (2006) Multidrug-resistance efflux pumps – not just for resistance. Nat Rev Microbiol 4(8):629–36PubMedCrossRefGoogle Scholar
  67. Poirel L, Kampfer P et al (2002) Chromosome-encoded Ambler class A beta-lactamase of Kluyvera georgiana, a probable progenitor of a subgroup of CTX-M extended-spectrum beta-lactamases. Antimicrob Agents Chemother 46(12):4038–40PubMedCrossRefGoogle Scholar
  68. Pomposiello PJ, Demple B (2000) Identification of SoxS-regulated genes in Salmonella enterica serovar typhimurium. J Bacteriol 182(1):23–9PubMedCrossRefGoogle Scholar
  69. Ricci V, Piddock LJ (2009) Ciprofloxacin selects for multidrug resistance in Salmonella enterica serovar Typhimurium mediated by at least two different pathways. J Antimicrob Chemother 63(5):909–16PubMedCrossRefGoogle Scholar
  70. Riesenfeld CS, Goodman RM et al (2004) Uncultured soil bacteria are a reservoir of new antibiotic resistance genes. Environ Microbiol 6(9):981–9PubMedCrossRefGoogle Scholar
  71. Robicsek A, Strahilevitz J et al (2006) Fluoroquinolone-modifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase. Nat Med 12(1):83–8PubMedCrossRefGoogle Scholar
  72. Roy PH (1999) Horizontal transfer of genes in bacteria. Microbiol Today 26:168–170Google Scholar
  73. Sandegren L, Andersson DI (2009) Bacterial gene amplification: implications for the evolution of antibiotic resistance. Nat Rev Microbiol 7(8):578–88PubMedCrossRefGoogle Scholar
  74. Shaw KJ, Miller N et al (2003) Comparison of the changes in global gene expression of Escherichia coli induced by four bactericidal agents. J Mol Microbiol Biotechnol 5(2):105–22PubMedCrossRefGoogle Scholar
  75. Sommer MO, Dantas G et al (2009) Functional characterization of the antibiotic resistance reservoir in the human microflora. Science 325(5944):1128–31PubMedCrossRefGoogle Scholar
  76. Soo VW, Hanson-Manful P et al (2011) From the cover: artificial gene amplification reveals an abundance of promiscuous resistance determinants in Escherichia coli. Proc Natl Acad Sci USA 108(4):1484–9PubMedCrossRefGoogle Scholar
  77. Spellberg B, Powers JH et al (2004) Trends in antimicrobial drug development: implications for the future. Clin Infect Dis 38(9):1279–86PubMedCrossRefGoogle Scholar
  78. Stogios PJ, Shakya T et al (2011) Structure and function of APH(4)-Ia, a hygromycin B resistance enzyme. J Biol Chem 286(3):1966–75PubMedCrossRefGoogle Scholar
  79. Strahilevitz J, Jacoby GA et al (2009) Plasmid-mediated quinolone resistance: a multifaceted threat. Clin Microbiol Rev 22(4):664–89PubMedCrossRefGoogle Scholar
  80. Toth M, Frase H et al (2010) Crystal structure and kinetic mechanism of aminoglycoside phosphotransferase-2″-IVa. Protein Sci 19(8):1565–76PubMedCrossRefGoogle Scholar
  81. Tu D, Blaha G et al (2005) Structures of MLSBK antibiotics bound to mutated large ribosomal subunits provide a structural explanation for resistance. Cell 121(2):257–70PubMedCrossRefGoogle Scholar
  82. Vetting MW, Park CH et al (2008) Mechanistic and structural analysis of aminoglycoside N-acetyltransferase AAC(6')-Ib and its bifunctional, fluoroquinolone-active AAC(6′)-Ib-cr variant. Biochemistry 47(37):9825–35PubMedCrossRefGoogle Scholar
  83. Walsh CT, Fisher SL et al (1996) Bacterial resistance to vancomycin: five genes and one missing hydrogen bond tell the story. Chem Biol 3:21–28PubMedCrossRefGoogle Scholar
  84. Ward SL, Hu Z et al (2004) Chalcomycin biosynthesis gene cluster from Streptomyces bikiniensis: novel features of an unusual ketolide produced through expression of the chm polyketide synthase in Streptomyces fradiae. Antimicrob Agents Chemother 48(12):4703–12PubMedCrossRefGoogle Scholar
  85. Waters B, Davies J (1997) Amino acid variation in the GyrA subunit of bacteria potentially associated with natural resistance to fluoroquinolone antibiotics. Antimicrob Agents Chemother 41(12):2766–9PubMedGoogle Scholar
  86. Wellman CH, Osterloff PL et al (2003) Fragments of the earliest land plants. Nature 425(6955):282–5PubMedCrossRefGoogle Scholar
  87. White DG, Goldman JD et al (1997) Role of the acrAB locus in organic solvent tolerance mediated by expression of marA, soxS, or robA in Escherichia coli. J Bacteriol 179(19):6122–6PubMedGoogle Scholar
  88. Whitman WB, Coleman DC et al (1998) Prokaryotes: the unseen majority. Proc Natl Acad Sci USA 95(12):6578–83PubMedCrossRefGoogle Scholar
  89. Williams KJ, Bax RP (2009) Challenges in developing new antibacterial drugs. Curr Opin Investig Drugs 10(2):157–63PubMedGoogle Scholar
  90. Wright GD (2007) The antibiotic resistome: the nexus of chemical and genetic diversity. Nat Rev Microbiol 5(3):175–86PubMedCrossRefGoogle Scholar
  91. Wright GD (2010) The antibiotic resistome. Expert Opin Drug Disc 5:779–788CrossRefGoogle Scholar
  92. Wu Z, Wright GD et al (1995) Overexpression, purification, and characterization of VanX, a D-D-dipeptidase which is essential for vancomycin resistance in Enterococcus faecium BM4147. Biochemistry 34(8):2455–63PubMedCrossRefGoogle Scholar
  93. Young PG, Walanj R et al (2009) The crystal structures of substrate and nucleotide complexes of Enterococcus faecium aminoglycoside-2″-phosphotransferase-IIa [APH(2″)-IIa] provide insights into substrate selectivity in the APH(2″) subfamily. J Bacteriol 191(13):4133–43PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease ResearchMcMaster UniversityHamiltonCanada

Personalised recommendations