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Plasmid-Mediated Quinolone Resistance

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Antimicrobial Drug Resistance

Abstract

Mutations that reduce target affinity or decrease drug accumulation are responsible for most of the increased quinolone resistance in gram-negative pathogens but do not account for how rapidly resistance has developed or its frequent linkage to resistance to other antimicrobial agents. Three mechanisms for plasmid-mediated quinolone resistance (PMQR), long thought not to occur, have been discovered since 1998. Plasmid genes qnrA, qnrB, qnrC, qnrD, qnrS, and qnrVC code for proteins of the pentapeptide repeat family that protect DNA gyrase and topoisomerase IV from quinolone inhibition. The qnr genes appear to have been acquired from aquatic bacteria, are usually associated on plasmids with mobilizing or transposable elements, and are often incorporated into sul1-type integrons. The second PMQR mechanism involves acetylation of certain quinolones by a variant of the common aminoglycoside acetyltransferase AAC(6′)-Ib. The third mechanism is enhanced efflux produced by plasmid genes for pumps QepAB and OqxAB. The plasmid-mediated mechanisms provide only low-level resistance that by itself does not exceed the clinical breakpoint for susceptibility but nonetheless facilitates selection of higher level resistance and makes pathogens containing PMQR genes harder to treat.

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References

  1. Neuhauser MM, Weinstein RA, Rydman R, Danziger LH, Karam G, Quinn JP. Antibiotic resistance among gram-negative bacilli in US intensive care units: implications for fluoroquinolone use. JAMA. 2003;289:885–8.

    Article  CAS  PubMed  Google Scholar 

  2. Martínez-Martínez L, Pascual A, Jacoby GA. Quinolone resistance from a transferable plasmid. Lancet. 1998;351:797–9.

    Article  PubMed  Google Scholar 

  3. Drlica K. The mutant selection window and antimicrobial resistance. J Antimicrob Chemother. 2003;52:11–7.

    Article  CAS  PubMed  Google Scholar 

  4. Jacoby GA. Mechanisms of resistance to quinolones. Clin Infect Dis. 2005;41 Suppl 2:S120–6.

    Article  CAS  PubMed  Google Scholar 

  5. Rodríguez-Martínez JM, Velasco C, García I, Cano ME, Martínez-Martínez L, Pascual A. Mutant prevention concentrations of fluoroquinolones for Enterobacteriaceae expressing the plasmid-carried quinolone resistance determinant qnrA1. Antimicrob Agents Chemother. 2007;51:2236–9.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Tran JH, Jacoby GA. Mechanism of plasmid-mediated quinolone resistance. Proc Natl Acad Sci U S A. 2002;99:5638–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tran JH, Jacoby GA, Hooper DC. Interaction of the plasmid-encoded quinolone resistance protein QnrA with Escherichia coli topoisomerase IV. Antimicrob Agents Chemother. 2005;49:3050–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hata M, Suzuki M, Matsumoto M, Takahashi M, Sato K, Ibe S, Sakae K. Cloning of a novel gene for quinolone resistance from a transferable plasmid in Shigella flexneri 2b. Antimicrob Agents Chemother. 2005;49:801–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jacoby GA, Walsh KE, Mills DM, Walker VJ, Oh H, Robicsek A, Hooper DC. qnrB, another plasmid-mediated gene for quinolone resistance. Antimicrob Agents Chemother. 2006;50:1178–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang M, Guo Q, Xu X, Wang X, Ye X, Wu S, Hooper DC, Wang M. New plasmid-mediated quinolone resistance gene, qnrC, found in a clinical isolate of Proteus mirabilis. Antimicrob Agents Chemother. 2009;53:1892–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cavaco LM, Hasman H, Xia S, Aarestrup FM. qnrD, a novel gene conferring transferable quinolone resistance in Salmonella enterica serovar Kentucky and Bovismorbificans strains of human origin. Antimicrob Agents Chemother. 2009;53:603–8.

    Article  CAS  PubMed  Google Scholar 

  12. Xia R, Guo X, Zhang Y, Xu H. qnrVC-like gene located in a novel complex class 1 integron harboring the ISCR1 element in an Aeromonas punctata strain from an aquatic environment in Shandong Province, China. Antimicrob Agents Chemother. 2010;54:3471–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Singh R, Rajpara N, Tak J, Patel A, Mohanty P, Vinothkumar K, Chowdhury G, Ramamurthy T, Ghosh A, Bhardwaj AK. Clinical isolates of Vibrio fluvialis from Kolkata, India, obtained during 2006: plasmids, the qnr gene and a mutation in gyrase A as mechanisms of multidrug resistance. J Med Microbiol. 2012;61:369–74.

    Article  CAS  PubMed  Google Scholar 

  14. Kim HB, Wang M, Ahmed S, Park CH, LaRocque RC, Faruque AS, Salam MA, Khan WA, Qadri F, Calderwood SB, Jacoby GA, Hooper DC. Transferable quinolone resistance in Vibrio cholerae. Antimicrob Agents Chemother. 2010;54:799–803.

    Article  CAS  PubMed  Google Scholar 

  15. Jacoby G, Cattoir V, Hooper D, Martínez-Martínez L, Nordmann P, Pascual A, Poirel L, Wang M. qnr gene nomenclature. Antimicrob Agents Chemother. 2008;52:2297–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rodríguez-Martínez JM, Velasco C, Briales A, García I, Conejo MC, Pascual A. Qnr-like pentapeptide repeat proteins in gram-positive bacteria. J Antimicrob Chemother. 2008;61:1240–3.

    Article  PubMed  Google Scholar 

  17. Sánchez MB, Hernández A, Rodríguez-Martínez JM, Martínez-Martínez L, Martínez JL. Predictive analysis of transmissible quinolone resistance indicates Stenotrophomonas maltophilia as a potential source of a novel family of Qnr determinants. BMC Microbiol. 2008;8:148–61.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Boulund F, Johnning A, Pereira MB, Larsson DG, Kristiansson E. A novel method to discover fluoroquinolone antibiotic resistance (qnr) genes in fragmented nucleotide sequences. BMC Genomics. 2012;13:695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jacoby GA, Hooper DC. Phylogenetic analysis of chromosomally determined Qnr and related proteins. Antimicrob Agents Chemother. 2013;57:1930–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tran JH, Jacoby GA, Hooper DC. Interaction of the plasmid-encoded quinolone resistance protein Qnr with Escherichia coli DNA gyrase. Antimicrob Agents Chemother. 2005;49:118–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hegde SS, Vetting MW, Roderick SL, Mitchenall LA, Maxwell A, Takiff HE, Blanchard JS. A fluoroquinolone resistance protein from Mycobacterium tuberculosis that mimics DNA. Science. 2005;308:1480–3.

    Article  CAS  PubMed  Google Scholar 

  22. Xiong X, Bromley EH, Oelschlaeger P, Woolfson DN, Spencer J. Structural insights into quinolone antibiotic resistance mediated by pentapeptide repeat proteins: conserved surface loops direct the activity of a Qnr protein from a gram-negative bacterium. Nucleic Acids Res. 2011;39:3917–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Vetting MW, Hegde SS, Wang M, Jacoby GA, Hooper DC, Blanchard JS. Structure of QnrB1, a plasmid-mediated fluoroquinolone resistance factor. J Biol Chem. 2011;286:25265–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hegde SS, Vetting MW, Mitchenall LA, Maxwell A, Blanchard JS. Structural and biochemical analysis of the pentapeptide repeat protein EfsQnr, a potent DNA gyrase inhibitor. Antimicrob Agents Chemother. 2011;55:110–7.

    Article  CAS  PubMed  Google Scholar 

  25. Robicsek A, Jacoby GA, Hooper DC. The worldwide emergence of plasmid-mediated quinolone resistance. Lancet Infect Dis. 2006;6:629–40.

    Article  CAS  PubMed  Google Scholar 

  26. Strahilevitz J, Jacoby GA, Hooper DC, Robicsek A. Plasmid-mediated quinolone resistance: a multifaceted threat. Clin Microbiol Rev. 2009;22:664–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fonseca EL, Dos Santos Freitas F, Vieira VV, Vicente AC. New qnr gene cassettes associated with superintegron repeats in Vibrio cholerae O1. Emerg Infect Dis. 2008;14:1129–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Strahilevitz J, Engelstein D, Adler A, Temper V, Moses AE, Block C, Robicsek A. Changes in qnr prevalence and fluoroquinolone resistance in clinical isolates of Klebsiella pneumoniae and Enterobacter spp. collected from 1990 to 2005. Antimicrob Agents Chemother. 2007;51:3001–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kim HB, Park CH, Kim CJ, Kim EC, Jacoby GA, Hooper DC. Prevalence of plasmid-mediated quinolone resistance determinants over a 9-year period. Antimicrob Agents Chemother. 2009;53:639–45.

    Article  CAS  PubMed  Google Scholar 

  30. Zhao X, Xu X, Zhu D, Ye X, Wang M. Decreased quinolone susceptibility in high percentage of Enterobacter cloacae clinical isolates caused only by Qnr determinants. Diagn Microbiol Infect Dis. 2010;67:110–3.

    Article  CAS  PubMed  Google Scholar 

  31. Poirel L, Rodriguez-Martinez JM, Mammeri H, Liard A, Nordmann P. Origin of plasmid-mediated quinolone resistance determinant QnrA. Antimicrob Agents Chemother. 2005;49:3523–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cattoir V, Poirel L, Mazel D, Soussy CJ, Nordmann P. Vibrio splendidus as the source of plasmid-mediated QnrS-like quinolone resistance determinants. Antimicrob Agents Chemother. 2007;51:2650–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jacoby GA, Griffin CM, Hooper DC. Citrobacter spp. as a source of qnrB alleles. Antimicrob Agents Chemother. 2011;55:4979–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Saga T, Sabtcheva S, Mitsutake K, Ishii Y, Tateda K, Yamaguchi K, Kaku M. Characterization of qnrB-like genes in Citrobacter species of the American Type Culture Collection. Antimicrob Agents Chemother. 2013;57:2863–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kim HB, Park CH, Gavin M, Jacoby GA, Hooper DC. Cold shock induces qnrA expression in Shewanella algae. Antimicrob Agents Chemother. 2011;55:414–6.

    Article  CAS  PubMed  Google Scholar 

  36. Wang M, Jacoby GA, Mills DM, Hooper DC. SOS regulation of qnrB expression. Antimicrob Agents Chemother. 2009;53:821–3.

    Article  CAS  PubMed  Google Scholar 

  37. Da Re S, Garnier F, Guerin E, Campoy S, Denis F, Ploy MC. The SOS response promotes qnrB quinolone-resistance determinant expression. EMBO Rep. 2009;10:929–33.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Briales A, Rodriguez-Martinez JM, Velasco C, Machuca J, Diaz de Alba P, Blazquez J, Pascual A. Exposure to diverse antimicrobials induces the expression of qnrB1, qnrD and smaqnr genes by SOS-dependent regulation. J Antimicrob Chemother. 2012;67:2854–9.

    Article  CAS  PubMed  Google Scholar 

  39. Okumura R, Liao CH, Gavin M, Jacoby GA, Hooper DC. Quinolone Induction of qnrVS1 in Vibrio splendidus and plasmid-carried qnrS1 in Escherichia coli, a mechanism independent of the SOS system. Antimicrob Agents Chemother. 2011;55:5942–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Robicsek A, Strahilevitz J, Jacoby GA, Macielag M, Abbanat D, Park CH, Bush K, Hooper DC. Fluoroquinolone-modifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase. Nat Med. 2006;12:83–8.

    Article  CAS  PubMed  Google Scholar 

  41. Vetting MW, Park CH, Hegde SS, Jacoby GA, Hooper DC, Blanchard JS. Mechanistic and structural analysis of aminoglycoside N-acetyltransferase AAC(6′)-Ib and its bifunctional fluoroquinolone-active AAC(6′)-Ib-cr variant. Biochemistry. 2008;47:9825–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Maurice F, Broutin I, Podglajen I, Benas P, Collatz E, Dardel F. Enzyme structural plasticity and the emergence of broad-spectrum antibiotic resistance. EMBO Rep. 2008;9:344–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yamane K, Wachino J, Suzuki S, Kimura K, Shibata N, Kato H, Shibayama K, Konda T, Arakawa Y. New plasmid-mediated fluoroquinolone efflux pump, QepA, found in an Escherichia coli clinical isolate. Antimicrob Agents Chemother. 2007;51:3354–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Périchon B, Courvalin P, Galimand M. Transferable resistance to aminoglycosides by methylation of G1405 in 16S rRNA and to hydrophilic fluoroquinolones by QepA-mediated efflux in Escherichia coli. Antimicrob Agents Chemother. 2007;51:2464–9.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Hansen LH, Johannesen E, Burmolle M, Sorensen AH, Sorensen SJ. Plasmid-encoded multidrug efflux pump conferring resistance to olaquindox in Escherichia coli. Antimicrob Agents Chemother. 2004;48:3332–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hansen LH, Jensen LB, Sorensen HI, Sorensen SJ. Substrate specificity of the OqxAB multidrug resistance pump in Escherichia coli and selected enteric bacteria. J Antimicrob Chemother. 2007;60:145–7.

    Article  CAS  PubMed  Google Scholar 

  47. Rodríguez-Martínez JM, Pichardo C, García I, Pachón-Ibañez ME, Docobo-Pérez F, Pascual A, Pachón J, Martínez-Martínez L. Activity of ciprofloxacin and levofloxacin in experimental pneumonia caused by Klebsiella pneumoniae deficient in porins, expressing active efflux and producing QnrA1. Clin Microbiol Infect. 2008;14:691–7.

    Article  PubMed  Google Scholar 

  48. Domínguez-Herrera J, Velasco C, Docobo-Pérez F, Rodríguez-Martínez JM, López-Rojas R, Briales A, Pichardo C, Díaz-de-Alba P, Rodríguez-Baño J, Pascual A, Pachón J. Impact of qnrA1, qnrB1 and qnrS1 on the efficacy of ciprofloxacin and levofloxacin in an experimental pneumonia model caused by Escherichia coli with or without the GyrA mutation Ser83Leu. J Antimicrob Chemother. 2013;68:1609–15.

    Article  PubMed  Google Scholar 

  49. Allou N, Cambau E, Massias L, Chau F, Fantin B. Impact of low-level resistance to fluoroquinolones due to qnrA1 and qnrS1 genes or a gyrA mutation on ciprofloxacin bactericidal activity in a murine model of Escherichia coli urinary tract infection. Antimicrob Agents Chemother. 2009;53:4292–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jakobsen L, Cattoir V, Jensen KS, Hammerum AM, Nordmann P, Frimodt-Moller N. Impact of low-level fluoroquinolone resistance genes qnrA1, qnrB19 and qnrS1 on ciprofloxacin treatment of isogenic Escherichia coli strains in a murine urinary tract infection model. J Antimicrob Chemother. 2012;67:2438–44.

    Article  CAS  PubMed  Google Scholar 

  51. Defife R, Scheetz MH, Feinglass JM, Postelnick MJ, Scarsi KK. Effect of differences in MIC values on clinical outcomes in patients with bloodstream infections caused by gram-negative organisms treated with levofloxacin. Antimicrob Agents Chemother. 2009;53:1074–9.

    Article  CAS  PubMed  Google Scholar 

  52. Chong YP, Choi SH, Kim ES, Song EH, Lee EJ, Park KH, Cho OH, Kim SH, Lee SO, Kim MN, Jeong JY, Woo JH, Kim YS. Bloodstream infections caused by qnr-positive Enterobacteriaceae: clinical and microbiologic characteristics and outcomes. Diagn Microbiol Infect Dis. 2010;67:70–7.

    Article  CAS  PubMed  Google Scholar 

  53. Liao CH, Hsueh P-R, Jacoby GA, Hooper DC. Risk factors and clinical characteristics of patients with qnr-positive Klebsiella pneumoniae bacteremia. J Antimicrob Chemother. 2013;68(12):2907–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Part-Time, Harvard Medical School, Boston, MA, USA

    George A. Jacoby M.D.

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  1. George A. Jacoby M.D.
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Correspondence to George A. Jacoby M.D. .

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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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Jacoby, G.A. (2017). Plasmid-Mediated Quinolone 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_17

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