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. 1997 Dec;41(12):2733–2737. doi: 10.1128/aac.41.12.2733

Mechanisms of fluoroquinolone resistance in genetically related strains of Staphylococcus aureus.

G W Kaatz 1, S M Seo 1
PMCID: PMC164198  PMID: 9420048

Abstract

Fluoroquinolone resistance in Staphylococcus aureus results from amino acid substitutions at particular locations in the DNA gyrase A and B subunits as well as in the topoisomerase IV A subunit and from NorA-mediated efflux. More than one resistance mechanism may be present in a single strain. Fluoroquinolone-resistant derivatives of SA-1199, a methicillin-susceptible S. aureus strain, were selected in vivo or in vitro, and their mechanisms of fluoroquinolone resistance were identified. We found that many of the resistance mechanisms described above can develop in derivatives of a single parent strain, either singly or in combination, and can arise in a single step. Variances in MICs for strains with the same apparent resistance mechanisms likely are due to the presence of new or undetected but established means of fluoroquinolone resistance. NorA-mediated resistance can occur in the apparent absence of topoisomerase mutations and in some strains may be the result of a promoter region mutation causing increased expression of norA. However, increased expression of norA can occur independently of this mutation, suggesting that a regulatory locus for this gene exists elsewhere on the chromosome.

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Selected References

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  1. Ahmed M., Borsch C. M., Neyfakh A. A., Schuldiner S. Mutants of the Bacillus subtilis multidrug transporter Bmr with altered sensitivity to the antihypertensive alkaloid reserpine. J Biol Chem. 1993 May 25;268(15):11086–11089. [PubMed] [Google Scholar]
  2. Chomczynski P. A reagent for the single-step simultaneous isolation of RNA, DNA and proteins from cell and tissue samples. Biotechniques. 1993 Sep;15(3):532-4, 536-7. [PubMed] [Google Scholar]
  3. Eliopoulos G. M., Klimm K., Eliopoulos C. T., Ferraro M. J., Moellering R. C., Jr In vitro activity of CP-99,219, a new fluoroquinolone, against clinical isolates of gram-positive bacteria. Antimicrob Agents Chemother. 1993 Feb;37(2):366–370. doi: 10.1128/aac.37.2.366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ferrero L., Cameron B., Crouzet J. Analysis of gyrA and grlA mutations in stepwise-selected ciprofloxacin-resistant mutants of Staphylococcus aureus. Antimicrob Agents Chemother. 1995 Jul;39(7):1554–1558. doi: 10.1128/aac.39.7.1554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ferrero L., Cameron B., Manse B., Lagneaux D., Crouzet J., Famechon A., Blanche F. Cloning and primary structure of Staphylococcus aureus DNA topoisomerase IV: a primary target of fluoroquinolones. Mol Microbiol. 1994 Aug;13(4):641–653. doi: 10.1111/j.1365-2958.1994.tb00458.x. [DOI] [PubMed] [Google Scholar]
  6. Goswitz J. J., Willard K. E., Fasching C. E., Peterson L. R. Detection of gyrA gene mutations associated with ciprofloxacin resistance in methicillin-resistant Staphylococcus aureus: analysis by polymerase chain reaction and automated direct DNA sequencing. Antimicrob Agents Chemother. 1992 May;36(5):1166–1169. doi: 10.1128/aac.36.5.1166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ito H., Yoshida H., Bogaki-Shonai M., Niga T., Hattori H., Nakamura S. Quinolone resistance mutations in the DNA gyrase gyrA and gyrB genes of Staphylococcus aureus. Antimicrob Agents Chemother. 1994 Sep;38(9):2014–2023. doi: 10.1128/aac.38.9.2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kaatz G. W., Seo S. M. Inducible NorA-mediated multidrug resistance in Staphylococcus aureus. Antimicrob Agents Chemother. 1995 Dec;39(12):2650–2655. doi: 10.1128/aac.39.12.2650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kaatz G. W., Seo S. M., Lamp K. C., Bailey E. M., Rybak M. J. CI-960, a new fluoroquinolone, for therapy of experimental ciprofloxacin-susceptible and -resistant Staphylococcus aureus endocarditis. Antimicrob Agents Chemother. 1992 Jun;36(6):1192–1197. doi: 10.1128/aac.36.6.1192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kaatz G. W., Seo S. M., Ruble C. A. Efflux-mediated fluoroquinolone resistance in Staphylococcus aureus. Antimicrob Agents Chemother. 1993 May;37(5):1086–1094. doi: 10.1128/aac.37.5.1086. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kaatz G. W., Seo S. M., Ruble C. A. Mechanisms of fluoroquinolone resistance in Staphylococcus aureus. J Infect Dis. 1991 May;163(5):1080–1086. doi: 10.1093/infdis/163.5.1080. [DOI] [PubMed] [Google Scholar]
  12. Neyfakh A. A., Borsch C. M., Kaatz G. W. Fluoroquinolone resistance protein NorA of Staphylococcus aureus is a multidrug efflux transporter. Antimicrob Agents Chemother. 1993 Jan;37(1):128–129. doi: 10.1128/aac.37.1.128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ng E. Y., Trucksis M., Hooper D. C. Quinolone resistance mediated by norA: physiologic characterization and relationship to flqB, a quinolone resistance locus on the Staphylococcus aureus chromosome. Antimicrob Agents Chemother. 1994 Jun;38(6):1345–1355. doi: 10.1128/aac.38.6.1345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ng E. Y., Trucksis M., Hooper D. C. Quinolone resistance mutations in topoisomerase IV: relationship to the flqA locus and genetic evidence that topoisomerase IV is the primary target and DNA gyrase is the secondary target of fluoroquinolones in Staphylococcus aureus. Antimicrob Agents Chemother. 1996 Aug;40(8):1881–1888. doi: 10.1128/aac.40.8.1881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Novick R. P. Genetic systems in staphylococci. Methods Enzymol. 1991;204:587–636. doi: 10.1016/0076-6879(91)04029-n. [DOI] [PubMed] [Google Scholar]
  16. Perichon B., Tankovic J., Courvalin P. Characterization of a mutation in the parE gene that confers fluoroquinolone resistance in Streptococcus pneumoniae. Antimicrob Agents Chemother. 1997 May;41(5):1166–1167. doi: 10.1128/aac.41.5.1166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  19. Sreedharan S., Oram M., Jensen B., Peterson L. R., Fisher L. M. DNA gyrase gyrA mutations in ciprofloxacin-resistant strains of Staphylococcus aureus: close similarity with quinolone resistance mutations in Escherichia coli. J Bacteriol. 1990 Dec;172(12):7260–7262. doi: 10.1128/jb.172.12.7260-7262.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Sugino A., Higgins N. P., Cozzarelli N. R. DNA gyrase subunit stoichiometry and the covalent attachment of subunit A to DNA during DNA cleavage. Nucleic Acids Res. 1980 Sep 11;8(17):3865–3874. doi: 10.1093/nar/8.17.3865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Takenouchi T., Ishii C., Sugawara M., Tokue Y., Ohya S. Incidence of various gyrA mutants in 451 Staphylococcus aureus strains isolated in Japan and their susceptibilities to 10 fluoroquinolones. Antimicrob Agents Chemother. 1995 Jul;39(7):1414–1418. doi: 10.1128/aac.39.7.1414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Yamagishi J., Kojima T., Oyamada Y., Fujimoto K., Hattori H., Nakamura S., Inoue M. Alterations in the DNA topoisomerase IV grlA gene responsible for quinolone resistance in Staphylococcus aureus. Antimicrob Agents Chemother. 1996 May;40(5):1157–1163. doi: 10.1128/aac.40.5.1157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Yoshida H., Bogaki M., Nakamura S., Ubukata K., Konno M. Nucleotide sequence and characterization of the Staphylococcus aureus norA gene, which confers resistance to quinolones. J Bacteriol. 1990 Dec;172(12):6942–6949. doi: 10.1128/jb.172.12.6942-6949.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]

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