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Mutations as a Basis of Antimicrobial Resistance

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Antimicrobial Drug Resistance

Abstract

The past three decades have witnessed a disturbing increase in antimicrobial resistance. Bacterial isolates are emerging that are resistant to all currently available antimicrobial agents. Bacteria with this phenotype are designated multidrug-resistant (MDR) or “pan-drug” resistant (PDR) strains. What is the genetic basis of this remarkable survival skill? Are advantageous changes in the genome always random? Is antibiotic pressure the cause of growing resistance rates or does it merely serve as a trigger that selects the archived defense armamentarium within bacteria? In this review we will explore these concepts and discuss: (1) genetic diversity and mutations as its basis and (2) “hyper-mutators” and the mechanisms responsible for high mutation rates. Our review will conclude with examples of specific point mutations in bacterial enzymes that confer resistance to certain antibiotic classes.

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References

  1. Luria SE, Delbruck M. Mutations of bacteria from virus sensitivity to virus resistance. Genetics. 1943;28(6):491–511.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Davis BB, Dulbecco R, Eisen HS, Ginsberg HS. Microbiology, 4th ed. J. B. Lippincot; 1990.

    Google Scholar 

  3. Friedberg E, Walker GC, Siede W. DNA repair and mutagenesis. Washington, DC: ASM Press; 1995.

    Google Scholar 

  4. Tippin B, Pham P, Goodman MF. Error-prone replication for better or worse. Trends Microbiol. 2004;12(6):288–95.

    Article  CAS  PubMed  Google Scholar 

  5. Lorian V. Antibiotics in laboratory medicine. Baltimore, MD: Lippincott Williams & Wilkins; 2002.

    Google Scholar 

  6. LeClerc JE, Li B, Payne WL, Cebula TA. High mutation frequencies among Escherichia coli and Salmonella pathogens. Science. 1996;274(5290):1208–11.

    Article  CAS  PubMed  Google Scholar 

  7. Oliver A, Baquero F, Blazquez J. The mismatch repair system (mutS, mutL and uvrD genes) in Pseudomonas aeruginosa: molecular characterization of naturally occurring mutants. Mol Microbiol. 2002;43(6):1641–50.

    Article  CAS  PubMed  Google Scholar 

  8. Radman M. Enzymes of evolutionary change. Nature. 1999;401(6756):866–7. 9.

    Article  CAS  PubMed  Google Scholar 

  9. Cirz RT, Chin JK, Andes DR, de Crecy-Lagard V, Craig WA, Romesberg FE. Inhibition of mutation and combating the evolution of antibiotic resistance. PLoS Biol. 2005;3(6), e176.

    Article  PubMed  PubMed Central  Google Scholar 

  10. O’Neill AJ, Chopra I. Use of mutator strains for characterization of novel antimicrobial agents. Antimicrob Agents Chemother. 2001;45(5):1599–600.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ennis DG, Fisher B, Edmiston S, Mount DW. Dual role for Escherichia coli RecA protein in SOS mutagenesis. Proc Natl Acad Sci U S A. 1985;82(10):3325–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yeiser B, Pepper ED, Goodman MF, Finkel SE. SOS-induced DNA polymerases enhance long-term survival and evolutionary fitness. Proc Natl Acad Sci U S A. 2002;99(13):8737–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pham P, Rangarajan S, Woodgate R, Goodman MF. Roles of DNA polymerases V and II in SOS-induced error-prone and error-free repair in Escherichia coli. Proc Natl Acad Sci U S A. 2001;98(15):8350–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tompkins JD, Nelson JL, Hazel JC, Leugers SL, Stumpf JD, Foster PL. Error-prone polymerase, DNA polymerase IV, is responsible for transient hypermutation during adaptive mutation in Escherichia coli. J Bacteriol. 2003;185(11):3469–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Friedberg EC, Wagner R, Radman M. Specialized DNA polymerases, cellular survival, and the genesis of mutations. Science. 2002;296(5573):1627–30.

    Article  CAS  PubMed  Google Scholar 

  16. Meroueh SO, Minasov G, Lee W, Shoichet BK, Mobashery S. Structural aspects for evolution of beta-lactamases from penicillin-binding proteins. J Am Chem Soc. 2003;125(32):9612–8.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Heisig P. Actions and resistance mechanisms of beta-lactam antibiotics. Penicillin-binding proteins, beta-3-lactamases and signal proteins. Pharm Unserer Zeit. 2006;35(5):400–8.

    Article  CAS  PubMed  Google Scholar 

  19. Goffin C, Ghuysen JM. Multimodular penicillin-binding proteins: an enigmatic family of orthologs and paralogs. Microbiol Mol Biol Rev. 1998;62(4):1079–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Hakenbeck R, Konig A, Kern I, et al. Acquisition of five high-Mr penicillin-binding protein variants during transfer of high-level beta-lactam resistance from Streptococcus mitis to Streptococcus pneumoniae. J Bacteriol. 1998;180(7):1831–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Dowson CG, Hutchison A, Spratt BG. Extensive re-modelling of the transpeptidase domain of penicillin-binding protein 2B of a penicillin-resistant South African isolate of Streptococcus pneumoniae. Mol Microbiol. 1989;3(1):95–102.

    Article  CAS  PubMed  Google Scholar 

  22. Hakenbeck R, Coyette J. Resistant penicillin-binding proteins. Cell Mol Life Sci. 1998;54(4):332–40.

    Article  CAS  PubMed  Google Scholar 

  23. Ligozzi M, Pittaluga F, Fontana R. Identification of a genetic element (psr) which negatively controls expression of Enterococcus hirae penicillin-binding protein 5. J Bacteriol. 1993;175(7):2046–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rice LB, Bellais S, Carias LL, et al. Impact of specific pbp5 mutations on expression of beta-lactam resistance in Enterococcus faecium. Antimicrob Agents Chemother. 2004;48(8):3028–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Drlica K, Zhao X. DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiol Mol Biol Rev. 1997;61(3):377–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Hooper DC. Mechanisms of fluoroquinolone resistance. Drug Resist Updates. 1999;2(1):38–55.

    Article  CAS  Google Scholar 

  27. Cole ST. Mycobacterium tuberculosis: drug-resistance mechanisms. Trends Microbiol. 1994;2(10):411–5.

    Article  CAS  PubMed  Google Scholar 

  28. Jin DJ, Gross CA. Mapping and sequencing of mutations in the Escherichia coli rpoB gene that lead to rifampicin resistance. J Mol Biol. 1988;202(1):45–58.

    Article  CAS  PubMed  Google Scholar 

  29. Martinez JL, Baquero F. Mutation frequencies and antibiotic resistance. Antimicrob Agents Chemother. 2000;44(7):1771–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Poole K, Tetro K, Zhao Q, Neshat S, Heinrichs DE, Bianco N. Expression of the multidrug resistance operon mexA-mexB-oprM in Pseudomonas aeruginosa: mexR encodes a regulator of operon expression. Antimicrob Agents Chemother. 1996;40(9):2021–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Ziha-Zarifi I, Llanes C, Kohler T, Pechere JC, Plesiat P. In vivo emergence of multidrug-resistant mutants of Pseudomonas aeruginosa overexpressing the active efflux system MexA-MexB-OprM. Antimicrob Agents Chemother. 1999;43(2):287–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Schnappinger D, Hillen W. Tetracyclines: antibiotic action, uptake, and resistance mechanisms. Arch Microbiol. 1996;165(6):359–69.

    Article  CAS  PubMed  Google Scholar 

  33. Chopra I, Roberts M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev. 2001;65(2):232–60; second page, table of contents.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Heuer C, Hickman RK, Curiale MS, Hillen W, Levy SB. Constitutive expression of tetracycline resistance mediated by a Tn10-like element in Haemophilus parainfluenzae results from a mutation in the repressor gene. J Bacteriol. 1987;169(3):990–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Reynolds PE. Structure, biochemistry and mechanism of action of glycopeptide antibiotics. Eur J Clin Microbiol Infect Dis. 1989;8(11):943–50.

    Article  CAS  PubMed  Google Scholar 

  36. Arthur M, Reynolds P, Courvalin P. Glycopeptide resistance in enterococci. Trends Microbiol. 1996;4(10):401–7.

    Article  CAS  PubMed  Google Scholar 

  37. Roberts MC, Sutcliffe J, Courvalin P, Jensen LB, Rood J, Seppala H. Nomenclature for macrolide and macrolide-lincosamide-streptogramin B resistance determinants. Antimicrob Agents Chemother. 1999;43(12):2823–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Lai CJ, Dahlberg JE, Weisblum B. Structure of an inducibly methylatable nucleotide sequence in 23S ribosomal ribonucleic acid from erythromycin-resistant Staphylococcus aureus. Biochemistry. 1973;12(3):457–60.

    Article  CAS  PubMed  Google Scholar 

  39. Weisblum B. Erythromycin resistance by ribosome modification. Antimicrob Agents Chemother. 1995;39(3):577–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Weisblum B, Demohn V. Erythromycin-inducible resistance in Staphylococcus aureus: survey of antibiotic classes involved. J Bacteriol. 1969;98(2):447–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Jacobs C, Frere JM, Normark S. Cytosolic intermediates for cell wall biosynthesis and degradation control inducible beta-lactam resistance in gram-negative bacteria. Cell. 1997;88(6):823–32.

    Article  CAS  PubMed  Google Scholar 

  42. Bennett PM, Chopra I. Molecular basis of beta-lactamase induction in bacteria. Antimicrob Agents Chemother. 1993;37(2):153–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jacobs C, Joris B, Jamin M, et al. AmpD, essential for both beta-lactamase regulation and cell wall recycling, is a novel cytosolic N-acetylmuramyl-L-alanine amidase. Mol Microbiol. 1995;15(3):553–9.

    Article  CAS  PubMed  Google Scholar 

  44. Thomson CJ, Amyes SG. TRC-1: emergence of a clavulanic acid-resistant TEM beta-lactamase in a clinical strain. FEMS Microbiol Lett. 1992;70(2):113–7.

    CAS  PubMed  Google Scholar 

  45. Ambler RP, Coulson AF, Frere JM, et al. A standard numbering scheme for the class A beta-lactamases. Biochem J. 1991;276(Pt 1):269–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nukaga M, Mayama K, Hujer AM, Bonomo RA, Knox JR. Ultrahigh resolution structure of a class A beta-lactamase: on the mechanism and specificity of the extended-spectrum SHV-2 enzyme. J Mol Biol. 2003;328(1):289–301.

    Article  CAS  PubMed  Google Scholar 

  47. Zhou XY, Bordon F, Sirot D, Kitzis MD, Gutmann L. Emergence of clinical isolates of Escherichia coli producing TEM-1 derivatives or an OXA-1 beta-lactamase conferring resistance to beta-lactamase inhibitors. Antimicrob Agents Chemother. 1994;38(5):1085–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Dubois V, Poirel L, Arpin C, et al. SHV-49, a novel inhibitor-resistant beta-lactamase in a clinical isolate of Klebsiella pneumoniae. Antimicrob Agents Chemother. 2004;48(11):4466–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Belaaouaj A, Lapoumeroulie C, Canica MM, et al. Nucleotide sequences of the genes coding for the TEM-like beta-lactamases IRT-1 and IRT-2 (formerly called TRI-1 and TRI-2). FEMS Microbiol Lett. 1994;120(1–2):75–80.

    CAS  PubMed  Google Scholar 

  50. Henquell C, Chanal C, Sirot D, Labia R, Sirot J. Molecular characterization of nine different types of mutants among 107 inhibitor-resistant TEM beta-lactamases from clinical isolates of Escherichia coli. Antimicrob Agents Chemother. 1995;39(2):427–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wang X, Minasov G, Shoichet BK. The structural bases of antibiotic resistance in the clinically derived mutant beta-lactamases TEM-30, TEM-32, and TEM-34. J Biol Chem. 2002;277(35):32149–56.

    Article  CAS  PubMed  Google Scholar 

  52. Robin F, Delmas J, Chanal C, Sirot D, Sirot J, Bonnet R. TEM-109 (CMT-5), a natural complex mutant of TEM-1 beta-lactamase combining the amino acid substitutions of TEM-6 and TEM-33 (IRT-5). Antimicrob Agents Chemother. 2005;49(11):4443–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sirot D, Recule C, Chaibi EB, et al. A complex mutant of TEM-1 beta-lactamase with mutations encountered in both IRT-4 and extended-spectrum TEM-15, produced by an Escherichia coli clinical isolate. Antimicrob Agents Chemother. 1997;41(6):1322–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Babic M, Hujer AM, Bonomo RA. What’s new in antibiotic resistance? Focus on beta-lactamases. Drug Resist Updat. 2006;9(3):142–56.

    Article  CAS  PubMed  Google Scholar 

  55. Bonnet R. Growing group of extended-spectrum beta-lactamases: the CTX-M enzymes. Antimicrob Agents Chemother. 2004;48(1):1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Huang W, Palzkill T. A natural polymorphism in beta-lactamase is a global suppressor. Proc Natl Acad Sci U S A. 1997;94(16):8801–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Farzaneh S, Chaibi EB, Peduzzi J, et al. Implication of Ile-69 and Thr-182 residues in kinetic characteristics of IRT-3 (TEM-32) beta-lactamase. Antimicrob Agents Chemother. 1996;40(10):2434–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Orencia MC, Yoon JS, Ness JE, Stemmer WP, Stevens RC. Predicting the emergence of antibiotic resistance by directed evolution and structural analysis. Nat Struct Biol. 2001;8(3):238–42.

    Article  CAS  PubMed  Google Scholar 

  59. Winkler ML, Bonomo RA. SHV-129: a gateway to global suppressors in the SHV beta-lactamase family? Mol Biol Evol. 2016;33(2):429–41.

    Article  CAS  PubMed  Google Scholar 

  60. Bradford PA. Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin Microbiol Rev. 2001;14(4):933–51, table of contents.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Aubert D, Poirel L, Chevalier J, Leotard S, Pages JM, Nordmann P. Oxacillinase-mediated resistance to cefepime and susceptibility to ceftazidime in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2001;45(6):1615–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Research reported in this presentation was directly supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers 5K08AI112506-02 (LKL), R01AI072219, R01AI063517, R01AI100560 (RAB), and by the Department of Veterans Affairs Research and Development under Award Number I01BX001974, VISN 10 Geriatrics Research, Education and Clinical Center (RAB).

The content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Veterans Affairs or the National Institutes of Health.

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Authors and Affiliations

  1. Pharmacology, Molecular Biology and Microbiology, University Hospitals Case Medical Center, Cleveland, OH, USA

    Robert A. Bonomo M.D. (Chief, Vice Chair for Veteran Affairs)

  2. Medical Service, Louis Stokes Cleveland Department of Veteran Affairs Medical Cente, University Hospitals Case Medical Center, Cleveland, OH, USA

    Robert A. Bonomo M.D. (Chief, Vice Chair for Veteran Affairs)

  3. Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH, USA

    Robert A. Bonomo M.D. (Chief, Vice Chair for Veteran Affairs)

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  1. Robert A. Bonomo M.D.
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Correspondence to Robert A. Bonomo M.D. .

Editor information

Editors and Affiliations

  1. Treiber Therapeutics, Cambridge, Massachusetts, USA

    Douglas L. Mayers

  2. Wayne State University School of Medicine, Detroit Medical Center, Detroit, Michigan, USA

    Jack D. Sobel

  3. Centre de recherche en Infectiologie, University of Laval, Quebec City, Canada

    Marc Ouellette

  4. Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Keith S. Kaye

  5. Infection Control and Prevention Unit of Infectious Diseases, Assaf Harofeh Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel

    Dror Marchaim

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Bonomo, R.A. (2017). Mutations as a Basis of Antimicrobial Resistance. In: Mayers, D., Sobel, J., Ouellette, M., Kaye, K., Marchaim, D. (eds) Antimicrobial Drug Resistance. Springer, Cham. https://doi.org/10.1007/978-3-319-46718-4_6

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