Skip to main content

Mechanisms of Quinolone resistance

Conclusion

Quinolone resistance is induced by mutations on quinolone target enzymes such as gyrase and topo IV, and by mutations that prevent drug accumulation as a result of changes in outer membrane proteins and/or activation of drug-efflux pumps. Mutations on the target enzymes usually cause resistance to quinolones specifically, but mutations affecting drug accumulation confer resistance to multiple drugs. In most cases a single mutation does not cause high-level resistance to quinolones, but multiple mutations do. As the frequency of each mutation is about 10−8, multiple mutations hardly occur at the same time. Therefore, mutants with high-level resistance are likely to emerge in a stepwise fashion. The most important clinical point is that mutants, even with low levels of resistance, must not be selected upon quinolone treatment. In this context, we must remember that some quinolone-resistant mutants may be selected not only by quinolone derivatives but also by other kinds of antimicrobial agents. The future usefulness of quinolones as antimicrobials may depend on how carefully antimicrobial agents including quinolones are used clinically.

This is a preview of subscription content, access via your institution.

References

  1. Satake S. Yearly change of drug susceptibility (1983–1992). In: Medical Information System Developing Center (eds) Drug susceptibility information 1993. Tokyo: Yakugyojihosha, 1993:45–57 (in Japanese).

    Google Scholar 

  2. Goldstein FW, Acar JF. Epidemiology of quinolone resistance: Europe and North and South America. Drugs 1995;49(suppl 2):36–42.

    PubMed  CAS  Google Scholar 

  3. Turnidge J. Epidemiology of quinolone resistance: Eastern hemisphere. Drugs 1995;49(suppl 2): 43–47.

    PubMed  CAS  Google Scholar 

  4. Konno M, Ubukata K. Present status of quinolone resistance. In: Ueda Y, Shimizu K, Konno M, Matsumoto F (eds) Quinolones. Tokyo: Life Science, 1991:75–84 (in Japanese).

    Google Scholar 

  5. Courvalin P. Plasmid-mediated 4-quinolone resistance: a real or apparent absence?. Antimicrob Agents Chemother 1990;34:681–684.

    PubMed  CAS  Google Scholar 

  6. Gellert M, Mizuuchi K, O'Dea MH, Nash HA. DNA gyrase: an enzyme that introduces superhelical turns into DNA. Proc.Natl Acad Sci USA 1976;73:3872–3876.

    PubMed  CAS  Google Scholar 

  7. Gellert M. DNA topoisomerases. Annu Rev Biochem 1981;50:879–910.

    PubMed  CAS  Google Scholar 

  8. Wang JC. DNA topoisomerases. Annu Rev Biochem 1985;54:665–697.

    PubMed  CAS  Google Scholar 

  9. Wang JC. DNA topoisomerases. Annu Rev Biochem 1996;65:635–692.

    PubMed  CAS  Google Scholar 

  10. Klevan L, Wang JC. Deoxyribonucleic acid gyrase-deoxyribonucleic acid complex containing 140 base pairs of deoxyribonucleic acid and an a2 b2 core. Biochemistry 1980;19:5229–5234.

    PubMed  CAS  Google Scholar 

  11. Swanberg SL, Wang JC. Cloning and sequencing of theEscherichia coli gyrA gene coding for the A subunit of DNA gyrase. J Mol Biol 1987;197:723–736.

    Google Scholar 

  12. Hussain K, Elliot EJ, Salmond GPC. The ParD- mutant ofEscherichia coli also carries agyrAam mutation. The complete sequence ofgyrA. Mol Microbiol 1987;1:259–273.

    PubMed  CAS  Google Scholar 

  13. Yoshida H, Kojima T, Yamagishi J, Nakamura S. Quinolone-resistant mutations of thegyrA gene ofEscherichia coli. Mol Gen Genet 1988;211:1–7.

    PubMed  CAS  Google Scholar 

  14. Yamagishi J, Yoshida H, Yamayoshi M, Nakamura S. Nalidixic acid-resistant mutations of thegyrB gene ofEscherichia coli. Mol Gen Genet 1986;204:367–373.

    PubMed  CAS  Google Scholar 

  15. Adachi T, Mizuuchi M, Robinson EA, Appella E, O'Dea MH, Gellert M, Mizuuchi K. DNA sequence of theE. coli gyrB gene: application of a new sequencing strategy. Nucleic Acids Res 1987;15:771–784.

    PubMed  CAS  Google Scholar 

  16. Sugino A, Cozzarelli NR. The intrinsic ATPase of DNA gyrase. J Biol Chem 1980;255:6299–6306.

    PubMed  CAS  Google Scholar 

  17. Maxwell A, Gellert M. Mechanistic aspects of DNA topoisomerases. Adv Protein Chem 1986;38:69–107.

    PubMed  CAS  Google Scholar 

  18. Gellert M, Mizuuchi K, O'Dea MH, Itoh T, Tomizawa J. Nalidixic acid resistance: a second genetic character involved in DNA gyrase activity. Proc Natl Acad Sci USA 1977;74:4772–4776.

    PubMed  CAS  Google Scholar 

  19. Sugino A, Peebles CL, Kreuzer KN, Cozzarelli NR. Mechanism of action of nalidixic acid: purification ofEscherichia coli nalA gene product and its relationship to DNA gyrase and a novel nicking and closing enzyme. Proc Natl Acad Sci USA 1977;74:4767–4771.

    PubMed  CAS  Google Scholar 

  20. Gellert M, O'Dea MH, Itoh T, Tomizawa J. Novobiocin and coumermycin inhibit DNA supercoiling catalyzed by DNA gyrase. Proc Natl Acad Sci USA 1976;73:4474–4478.

    PubMed  CAS  Google Scholar 

  21. Yamagishi J, Yoshida H, Yamayoshi M, Nakamura S. Nalidixic acid-resistant mutations of thegyrB gene ofEscherichia coli. Mol Gen Genet 1986;204:367–373.

    PubMed  CAS  Google Scholar 

  22. Yoshida H, Bogaki M, Nakamura M, Nakamura S. Quinolone resistance- determining region in the DNA gyrasegyrA gene ofEscherichia coli. Antimicrob Agents Chemother 1990;34:1271–1272.

    PubMed  CAS  Google Scholar 

  23. Nakamura S, Nakamura M, Kojima T, Yoshida H.gyrA andgyrB mutations in quinolone-resistant strains ofEscherichia coli. Antimicrob Agents Chemother 1989;33:254–255.

    PubMed  CAS  Google Scholar 

  24. Cambau E, Borden F, Collatz E, Gutmann L. NovelgyrA point mutation in a strain ofEscherichia coli resistant to fluoroquinolones but not to nalidixic acid. Antimicrob Agents Chemother 1993;37:1247–1252.

    PubMed  CAS  Google Scholar 

  25. Cullen ME, Wyke AW, Kuroda R, Fisher LM. Cloning and characterization of a DNA gyrase A gene fromEscherichia coli that confers clinical resistance to 4-quinolones. Antimicrob Agents Chemother 1989;33:886–894.

    PubMed  CAS  Google Scholar 

  26. Heisig P, Schedletzky H, Falkenstein-Paul H. Mutations in thegyrA gene of a highly fluoroquinolone-resistant clinical isolate ofEscherichia coli. Antimicrob Agents Chemother 1993;37:696–701.

    PubMed  CAS  Google Scholar 

  27. Oram M, Fisher LM. 4-Quinolone resistance mutations in the DNA gyrase ofEscherichia coli clinical isolates identified by using the polymerase chain reaction. Antimicrob Agents Chemother 1991;35:387–389.

    PubMed  CAS  Google Scholar 

  28. Vila J, Ruiz J, Marco F, Barcelo A, Goni P, Giralt E, De Anta TJ. Association between double mutation in thegyrA gene of ciprofloxacin resistant clinical isolates ofEscherichia coli and MICs. Antimicrob Agents Chemother 1994;38: 2477–2479.

    PubMed  CAS  Google Scholar 

  29. Truong QC, Van J-CN, Shlaes D, Gutmann L, Moreau NJ. A novel, double mutation in DNA gyrase A ofEscherichia coli conferring resistance to quinolone antibiotics. Antimicrob Agents Chemother 1997;41:85–90.

    PubMed  CAS  Google Scholar 

  30. Griggs DJ, Gensberg K, Piddock LJV. Mutations ingyrA gene of quinolone- resistantSalmonella serotypes isolated from humans and animals. Antimicrob Agents Chemother 1996;40:1009–1013.

    PubMed  CAS  Google Scholar 

  31. Reyna F, Huesca M, Gonzalez V, Fuchs LY.Salmonella typhimurium gyrA mutations associated with fluoroquinolone resistance. Antimicrob Agents Chemother 1995;39:1621–1623.

    PubMed  CAS  Google Scholar 

  32. Rahman M, Mauff G, Levy J, Couturier M, Pulverer G, Butzler JP. Detection of 4-quinolone resistance mutation ingyrA gene ofShigella dysenteriae type 1 by PCR. Antimicrob Agents Chemother 1994;38:2488–2491.

    PubMed  CAS  Google Scholar 

  33. Vila J, Ruiz J, Goni P, Marcos A, De Anta TJ. Mutation in thegyrA gene of quinolone-resistant clinical isolates ofAcinetobacter baumannii. Antimicrob Agents Chemother 1995;39:1201–1203.

    PubMed  CAS  Google Scholar 

  34. Oppengaard H, Sorum H.gyrA mutations in quinolone-resistant isolates of fish pathogenAeromonas salmonicida. Antimicrob Agents Chemother 1994;38:2460–2464.

    Google Scholar 

  35. Hasegawa Y, Kobayashi T, Zouga T, Shimazu M, Nishida M. Resistance mutations ofPseudomonas aeruginosa clinical isolates in the presence of fluoroquinolones. J Jpn Assoc Infect Dis 1996;70:123–131 (in Japanese).

    CAS  Google Scholar 

  36. Kureishi A, Diver JM, Beckthold B, Schollaardt T, Bryan LE. Cloning and nucleotide sequence ofPseudomonas aeruginosa DNA gyrasegyrA gene from strain PAO1 and quinolone-resistant clinical isolates. Antimicrob Agents Chemother 1994;38:1944–1952.

    PubMed  CAS  Google Scholar 

  37. Yonezawa M, Takahata M, Matsubara N, Watanabe Y, Narita H. DNA gyrasegyrA mutations in quinolone-resistant clinical isolates ofPseudomonas aeruginosa. Antimicrob Agents Chemother 1995;39:1970–1972.

    PubMed  CAS  Google Scholar 

  38. Ando S, Katayama T, Hayakawa S, Ishikawa K, Horiba M, Yanaoka M, et al. Quinolone resistance mutations inKlebsiella pneumoniae. Chemotherapy (Tokyo) 1997;45: 670–675 (in Japanese).

    CAS  Google Scholar 

  39. Dimri GP, Das HK. Cloning and sequence analysis ofgyr gene ofKlebsiella pneumoniae. Nucleic Acids Res 1990;18:151–156.

    PubMed  CAS  Google Scholar 

  40. Deguchi T, Fukuoka A, Yasuda M, Nakano M, Ozeki S, Kanematsu E, Nishino Y, Ishihara S, Ban Y, Kawada Y. Alterations in the GyrA subunit of DNA gyrase and the ParC subunit of topoisomerase IV in quinolone-resistant clinical isolates ofKlebsiella pneumoniae. Antimicrob Agents Chemother 1997;41:699–701.

    PubMed  CAS  Google Scholar 

  41. Wang Y, Huang WM, Taylor DE. Cloning and nucleotide sequence of theCampylobacter jejuni gyrA gene and characterization of quinolone resistance mutations. Antimicrob Agents Chemother 1993;37:457–463.

    PubMed  CAS  Google Scholar 

  42. Talor DE, Chau AS-S. Cloning and nucleotide sequence of thegyrA gene fromCampylobacter fetus subsp.fetus ATCC27374 and characterization of ciprofloxacinresistant laboratory and clinical isolates. Antimicrob Agents Chemother 1997;41:665–671.

    Google Scholar 

  43. Belland RJ, Morrison SG, Ison C, Huang WM.Neisseria gonorrhoeae acquires mutations in analogous regions ofgyrA andparC in fluoroquinolone-resistant isolates. Mol Microbiol 1994;14:371–380.

    PubMed  CAS  Google Scholar 

  44. Deguchi T, Yasuda M, Asano M, Tada K, Iwata H, Komeda H, et al. DNA gyrase mutations in quinolone-resistant clinical isolates ofNeisseria gonorrhoeae. Antimicrob Agents Chemother 1995;39:561–563.

    PubMed  CAS  Google Scholar 

  45. Deguchi T, Yasuda M, Nakano M, Tada K, Ozeki S, Ezaki T, et al. Quinolone-resistantNeisseria gonorrhoeae: corrélation of alterations in the GyrA subunit of DNA gyrase and the ParC subunit of topoisomerase IV with antimicrobial susceptibility profiles. Antimicrob Agents Chemother 1996;40:1020–1023.

    PubMed  CAS  Google Scholar 

  46. Onodera S, Kishimoto K, Kiyota H, Goto H, Igarashi H, Kawahara G,et al. Analysis of resistance mechanism in new quinolone-resistantNeisseria gonorrhoeae. J Jpn Assoc Infect Dis 1995;69:511–516 (in Japanese).

    CAS  Google Scholar 

  47. Moore RA, Beckthold B, Wong S, Kureishi A, Bryan LE. Nucleotide sequence of thegyrA gene and characterization of ciprofloxacin-resistant mutants ofHelicobacter pylori. Antimicrob Agents Chemother 1995;39:107–111.

    PubMed  CAS  Google Scholar 

  48. Musso D, Drancourt M, Osscini S, Raoult D. Sequence of quinolone resistance-determining region ofgyrA gene for clinical isolates and for an in vitro-selected quinolone-resistant strain ofCoxiella burnetii. Antimicrob Agents Chemother 1996;40:870–873.

    PubMed  CAS  Google Scholar 

  49. Goswitz JJ, Willard KE, Fasching CE, Peterson LR. Detection ofgyrA gene mutations associated with ciprofloxacin resistance in methicillin-resistantStaphylococcus aureus: analysis by polymerase chain reaction and automated direct DNA sequencing. Antimicrob Agents Chemother 1992;36:1166–1169.

    PubMed  CAS  Google Scholar 

  50. Ito H, Yoshida H, Bogaki-Shonai M, Niga T, Hattori H, Nakamura S. Quinolone resistance mutations in the DNA gyrasegyrA andgyrB genes ofStaphylococcus aureus. Antimicrob Agents Chemother 1994;38:2014–2023.

    PubMed  CAS  Google Scholar 

  51. Sreedharan S, Oram M, Jensen B, Peterson LR, Fisher LM. DNA gyrasegyrA mutations in ciprofloxacin-resistant strains ofStaphylococcus aureus. Close similarity with quinolone resistance mutations inEscherichia coli. J Bacteriol 1990;172:7260–7262.

    PubMed  CAS  Google Scholar 

  52. Takenouchi T, Ishii G, Sugawara M, Tokue Y, Ohya S. Incidence of variousgyrA mutants in 451Staphylococcus aureus strains isolated in Japan and their susceptibilities to 10 fluoroquinolones. Antimicrob Agents Chemother 1995;39: 1414–1418.

    PubMed  CAS  Google Scholar 

  53. Tokue Y, Sugano K, Saito D, Noda T, Ohkura H, Shimosato Y, Sekiya T. Detection of novel mutations in thegyrA gene ofStaphylococcus aureus by nonradioisotopic single-strand conformation polymorphism analysis and direct DNA sequencing. Antimicrob Agents Chemother 1994;38:428–431.

    PubMed  CAS  Google Scholar 

  54. Tankovic J, Perichon B, Duval J, Courvalin P. Contribution of mutations ingyrA andparC genes to fluoroquinolone resistance of mutants ofStreptococcus pneumoniae obtained in vivo and in vitro. Antimicrob Agents Chemother 1996;40: 2505–2510.

    PubMed  CAS  Google Scholar 

  55. Munoz R, De La Campa AG. ParC subunit of DNA topoisomerase IV ofStreptococcus pneumoniae is a primary target of fluoroquinolones and cooperates with DNA gyrase A subunit in forming resistance phenotype. Antimicrob Agents Chemother 1996;40:2252–2257.

    PubMed  CAS  Google Scholar 

  56. Pan X-S, Ambler J, Mehtar S, Fisher LM. Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets inStreptococcus pneumoniae. Antimicrob Agents Chemother 1996;40:2321–2326.

    PubMed  CAS  Google Scholar 

  57. Gootz J, Zaniewski R, Haskell S, Schmieder B, Tankovic J, Girard D, et al. Activity of the new fluoroquinolone trovafloxacin (CP-99,219) against DNA gyrase and topoisomerase IV mutants ofStreptococcus pneumoniae selected in vitro. Antimicrob Agents Chemother 1996;40: 2691–2697.

    PubMed  CAS  Google Scholar 

  58. Janoir C, Zeller V, Kitzis M-D, Moreau NJ, Gutmann L. High-level fluoroquinolone resistance inStreptococcus pneumoniae requires mutations inparC andgyrA. Antimicrob Agents Chemother 1996;40:2760–2764.

    PubMed  CAS  Google Scholar 

  59. Korten V, Huang WM, Murray BE. Analysis by PCR and direct DNA sequencing ofgyrA mutations associated with fluoroquinolone resistance inEnterococcus faecalis. Antimicrob Agents Chemother 1994;38:2091–2094.

    PubMed  CAS  Google Scholar 

  60. Tankovic J, Mahjoubi F, Courvalin P, Duval J, Leclercq R. Development of fluoroquinolone resistance inEnterococcus faecalis and role of mutations in the DNA gyrasegyrA gene. Antimicrob Agents Chemother 1996;40:2558–2561.

    PubMed  CAS  Google Scholar 

  61. Alangaden GJ, Manavathu EK, Vakulenko SB, Zvonok NM, Lerner SA. Characterization of fluoroquinolone-resistant mutant strains ofMycobacterium tuberculosis selected in the laboratory and isolated from patients. Antimicrob Agents Chemother 1995;39:1700–1703.

    PubMed  CAS  Google Scholar 

  62. Takiff HE, Salazar I, Guerrero C, Philipp W, Huang WM, Kreiswirth B, et al. Cloning and nucleotide sequence ofMycobacterium tuberculosis gyrA andgyrB genes and detection of quinolone resistance mutations. Antimicrob Agents Chemother 1994;38:773–780.

    PubMed  CAS  Google Scholar 

  63. Bebear CM, Bove JM, Bebear C, Renaudin J. Characterization ofMycoplasma hominis mutations involved in resistance to fluoroquinolones. Antimicrob Agents Chemother 1997;41:269–273.

    PubMed  CAS  Google Scholar 

  64. Cozzarelli NR. DNA gyrase and the supercoiling of DNA. Science 1980;207:953–960.

    PubMed  CAS  Google Scholar 

  65. Yoshida H, Bogaki M, Nakamura M, Yamanaka LM, Nakamura S. Quinolone resistance-determining region in the DNA gyrasegyrB gene ofEscherichia coli. Antimicrob Agents Chemother 1991;35:1647–1650.

    PubMed  CAS  Google Scholar 

  66. Stein DC, Danaher RJ, Cook TM. Characterization of agyrB mutation responsible for low-level nalidixic acid resistance inNeisseria gonorrhoeae. Antimicrob Agents Chemother 1991;35:622–626.

    PubMed  CAS  Google Scholar 

  67. Shen LL, Kohlbrenner WE, Weigl D, Baranowski J. Mechanism of quinolone inhibition of DNA gyrase. J Biol Chem 1989;264:2973–2978.

    PubMed  CAS  Google Scholar 

  68. Yoshida H, Nakamura M, Bogaki M, Ito H, Kojima T, Hattori H, Nakamura S. Mechanism of action of quinolones againstEscherichia coli DNA gyrase. Antimicrob Agents Chemother 1993;37:839–845.

    PubMed  CAS  Google Scholar 

  69. Willmott CJR, Maxwell A. A single point mutation in the DNA gyrase A protein greatly reduces binding of fluoroquinolones to the gyrase-DNA complex. Antimicrob Agents Chemother 1993;37:126–127.

    PubMed  CAS  Google Scholar 

  70. Morais Cabral JH, Jackson AP, Smith CV, Shikotra N, Maxwell A, Liddington RC. Crystal structure of the breakage-reunion domain of DNA gyrase. Nature 1997; 388:903–906.

    PubMed  CAS  Google Scholar 

  71. Kato J, Nishimura Y, Imamura R, Niki H, Hiraga S, Suzuki H. New topoisomerase essential for chromosome segregation inE. coli. Cell 1990;63:393–404.

    PubMed  CAS  Google Scholar 

  72. Peng H, Marians KJ.Escherichia coli topoisomerase IV. Purification, characterization, subunit structure, and subunit interactions. J Biol Chem 1993;268:24481–24490.

    PubMed  CAS  Google Scholar 

  73. Adams DE, Shekhtman EM, Zechiedrich EL, Schmid MB, Cozzarelli NR. The role of topoisomerase IV in partitioning bacterial replicons and the structure of catenated intermediates in DNA replication. Cell 1992;71:277–288.

    PubMed  CAS  Google Scholar 

  74. Khodursky AB, Zechiedrich EL, Cozzarelli NR. Topoisomerase IV is a target of quinolones inEscherichia coli. Proc Natl Acad Sci USA 1995;92:11801–11805.

    PubMed  CAS  Google Scholar 

  75. Hoshino K, Kitamura A, Morrissey I, Sato K, Kato J, Ikeda H. Comparison of inhibition ofEscherichia coli topoisomerase IV by quinolones with DNA gyrase inhibition. Antimicrob Agents Chemother 1994;38:2623–2627.

    PubMed  CAS  Google Scholar 

  76. Kumagai Y, Kato J, Hoshino K, Akasaka T, Sato K, Ikeda H. Mutants ofEscherichia coli DNA topoisomerase IVparC gene. Antimicrob Agents Chemother 1996;40:710–714.

    PubMed  CAS  Google Scholar 

  77. Heisig P. Genetic evidence for a role ofparC mutations in development of high-level fluoroquinolone resistance inEscherichia coli. Antimicrob Agents Chemother 1996;40: 879–885.

    PubMed  CAS  Google Scholar 

  78. Belland RJ, Morrison SG, Ison C, Huang WM.Neisseria gonorrhoeae acquires mutations in analoqous regions ofgyrA andparC in fluoroquinolone-resistant isolates. Mol Microbiol 1994;14:371–380.

    PubMed  CAS  Google Scholar 

  79. Deguchi T, Yasuda M, Nakano M, Ozeki S, Ezaki T, Saito I, Kawada Y. Quinolone-resistantNeisseria gonorrhoeae: Correlation of alterations in the GyrA subunit of DNA gyrase and the ParC subunit of topoisomerase IV with antimicrobial susceptibility profiles. Antimicrob Agents Chemother 1996;40:1020–1023.

    PubMed  CAS  Google Scholar 

  80. Ferrero L, Cameron B, Manse B, Lagneaux D, Crouzet J, Famechon A, Blanche F. Cloning and primary structure ofStaphylococcus aureus DNA topoisomerase IV: a primary target of fluoroquinolones. Mol Microbiol 1994;13: 641–653.

    PubMed  CAS  Google Scholar 

  81. Ferrero L, Cameron B, Crouzet J. Analysis ofgyrA andgrlA mutations in stepwise-selected ciprofloxacin-resistant mutants ofStaphylococcus aureus. Antimicrob Agents Chemother 1995;39:1554–1558.

    PubMed  CAS  Google Scholar 

  82. Yamagishi J, Kojima T, Oyamada Y, Fujimoto K, Hattori H, Nakamura S, Inoue M. Alterations in the DNA topoisomerase IVgrlA gene responsible for quinolone resistance inStaphylococcus aureus. Antimicrob Agents Chemother 1996;40:1157–1163.

    PubMed  CAS  Google Scholar 

  83. Oizumi N, Kawabata S, Hirano M. Studies on the mechanism of action of nadifloxacin against quinolone-resistant clinical isolates ofStaphylococcus aureus. In: Program and Abstracts of the 44th General Meeting of Western Branch of Japan Society of Chemotherapy. Gifu. December 5–6. 1996: (abstr 31) (In Japanese).

  84. Ng EY, Trucksis M, Hooper DC. Quinolone resistance mutations in topoisomerase IV: Relationship to theflaqA locus and genetic evidence that topoisomerase IV is the primary target and DNA gyrase is the secondary target of fluoroquinolones inStaphylococcus aureus. Antimicrob Agents Chemother 1996;40:1881–1888.

    PubMed  CAS  Google Scholar 

  85. Pan X-S, Fisher LM. Cloning and characterization of theparC andparE genes ofStreptococcus pneumoniae encoding DNA topoisomerase IV: Role in fluoroquinolone resistance. J Bacteriol 1996;178:4060–4069.

    PubMed  CAS  Google Scholar 

  86. Pan X-S, Fisher LM. Targeting of DNA gyrase inStreptococcus pneumoniae by sparfloxacin: Selective targeting of gyrase or topoisomerase IV by quinolones. Antimicrob Agents Chemother 1997;41:471–474.

    PubMed  CAS  Google Scholar 

  87. Fukuda H, Hori S, Hiramatsu K. ThegrlA mutation in norfloxacin-resistant first-step mutants and clinical isolates ofStaphylococcus aureus. J Infect Chemother 1996;2:98–101.

    CAS  Google Scholar 

  88. Breines DM, Ouabdesselam S, Ng EY, Tankovic J, Shah S, Soussy CJ, Hooper DC. Quinolone resistance locusnfxD ofEscherichia coli is a mutant allele of theparE gene encoding a subunit of topoisomerase IV. Antimicrob Agents Chemother 1997;41:175–179.

    PubMed  CAS  Google Scholar 

  89. Perichon B, Tankovic J, Courvalin P. Characterization of a mutation in theparE gene that confers fluoroquinolone resistance inStreptococcus pneumoniae. Antimicrob Agents Chemother 1997;41:1166–1167.

    PubMed  CAS  Google Scholar 

  90. Hane M., Wood T.Escherichia coli K-12 mutants resistant to nalidixic acid: genetic mapping and dominance studies. J Bacteriol 1969;99:238–241.

    PubMed  CAS  Google Scholar 

  91. Bourguignon GJ, Levitt M, Sternglanz R. Studies on the mechanism of action of nalidixic acid. Antimicrob Agents Chemother 1973;4:479–486.

    PubMed  CAS  Google Scholar 

  92. Hrebenda J, Heleszko H, Brzostek K, Bielecki J. Mutation affecting resistance ofEscherichia coli to nalidixic acid. J Gen Microbiol 1985;131:2285–2292.

    PubMed  CAS  Google Scholar 

  93. Hooper DC, Wolfson JS. Mechanism of bacterial resistance to quinolones. In: Hooper DC, Wolfson JS (eds) Quinolone Antimicrob Agents 2nd ed. Washington: American Society for Microbiology, 1993:97–118.

    Google Scholar 

  94. Hirai K, Aoyama H, Suzue S, Irikura T, Iyobe S, Mitsuhashi S. Isolation and characterization of norfloxacin-resistant mutants ofEscherichia coli K-12. Antimicrob Agents Chemother 1986;30:248–253.

    PubMed  CAS  Google Scholar 

  95. Hooper DC, Wolfson JS, Souza KS, Tung C, McHugh GL, Swartz N. Genetic and biochemical characterization of norfloxacin resistance inEscherichia coli. Antimicrob Agents Chemother 1986;29:639–644.

    PubMed  CAS  Google Scholar 

  96. Hooper DC, Wolfson JS, Bozza MA, Ng EY. Genetics and regulation of outer membrane protein expression by quinolone resistance locinfxB, nfxC, andcfxB. Antimicrob Agents Chemother 1992;36:1151–1154.

    PubMed  CAS  Google Scholar 

  97. Hooper DC, Wolfson JS, Souza KS, Ng EY, McHugh GL, Swartz N. Mechanisms of quinolone resistance inEscherichia coli: Characterization ofnfxB andcfxB, two mutant resistance loci decreasing norfloxacin accumulation. Antimicrob Agents Chemother 1989;33:283–290.

    PubMed  CAS  Google Scholar 

  98. Matsuyama S, Mizushima S. Construction and characterization of a deletion mutant lackingmicF, a proposed regulatory gene for OmpF synthesis inEscherichia coli. J Bacteriol 1985;162:1196–1202.

    PubMed  CAS  Google Scholar 

  99. Ariza RR, Cohen SP, Bachhawat N, Levy SB, Demple B. Repressor mutations in themarRAB operon that activate oxidative stress genes and multiple antibiotic resistance inEscherichia coli. J Bacteriol 1994;176:143–148.

    PubMed  CAS  Google Scholar 

  100. George AM, Levy SB. Amplifiable resistance to tetracycline, chloramphenicol, and other antibiotics inEscherichia coli: involvement of a non-plasmid-determined efflux of tetracycline. J Bacteriol 1983;155:531–540.

    PubMed  CAS  Google Scholar 

  101. Cohen SP, Mcmurry LM, Hooper DC, Wolfson JS, Levy S. Cross-resistance to fluoroquinolones in multiple-antibiotic resistant (Mar)Escherichia coli selected by tetracycline or chloramphenicol: decreased drug accumulation associated with membrane changes in addition to OmpF reduction. Antimicrob Agents Chemother 1989;33:1318–1325.

    PubMed  CAS  Google Scholar 

  102. Nikaido H. Prevention of drug access to bacterial targets: permeability barriers and active efflux. Science 1994;264: 382–388.

    PubMed  CAS  Google Scholar 

  103. Cohen S, Hachler H, Levy SB. Genetic and functional analysis of the multiple antibiotic resistance (mar) locus inEscherichia coli. J Bacteriol 1993;175:1484–1492.

    PubMed  CAS  Google Scholar 

  104. Jair K-W, Martin RG, Rosner JL, Fujita N, Ishihama A, Worf Jr RE. Purification and regulatory properties of MarA protein, a transcriptional activator ofEscherichia coli multiple antibiotic and superoxide resistance promoters. J Bacteriol 1995;177:7100–7104.

    PubMed  CAS  Google Scholar 

  105. Gambino L, Gracheck SJ, Miller PF. Overexpression of the MarA positive regulator is sufficient to confer multiple antibiotic resistance inEscherichia coli. J Bacteriol 1993;175:2888–2894.

    PubMed  CAS  Google Scholar 

  106. Greenberg JT, Monach P, Chou JH, Josephy PD, Demple B. Positive control of a global antioxidant defence regulon activated by superoxide-generating agents inEscherichia coli. Proc Natl Acad Sci USA 1990;87:6181–6185.

    PubMed  CAS  Google Scholar 

  107. Greenberg JT, Chou JH, Monach PA, Demple B. Activation of oxidative stress genes by mutations at thesoxQ/ cfxB/marA locus ofEscherichia coli. J Bacteriol 1991;173: 4433–4439.

    PubMed  CAS  Google Scholar 

  108. Chou JH, Greenberg JT, Demple B. Posttranscriptional repression ofEscherichia coli OmpF protein in response to redox stress: positive control of themicF antisense RNA by thesoxRS locus. J Bacteriol 1993;175:1026–1031.

    PubMed  CAS  Google Scholar 

  109. Miller PF, Gambino LF, Sulavik MC, Gracheck SJ. Genetic relationship betweensoxRS andmar loci in promoting multiple antibiotic resistance inEscherichia coli. Antimicrob Agents Chemother 1994;38:1773–1779.

    PubMed  CAS  Google Scholar 

  110. Lomovskaya O, Lewis K.emr, anEscherichia coli locus for multidrug resistance. Proc Natl Acad Sci USA 1992; 89:8938–8942.

    PubMed  CAS  Google Scholar 

  111. Lomovskaya O, Kawai F, Matin A. Differential regulation of themcb andemr operons ofEscherichia coli: role ofmcb in multidrug resistance. Antimicrob Agents Chemother 1996;40:1050–1052.

    PubMed  CAS  Google Scholar 

  112. Ariza RR, Li Z, Ringstad N, Demple B. Activation of multiple antibiotic resistance and binding of stress-inducible promoters byEscherichia coli Rob protein. J Bacteriol 1995;177:1655–1661.

    PubMed  CAS  Google Scholar 

  113. Rella M, Haas D. Resistance ofPseudomonas aeruginosa PAO to nalidixic acid and low levels of β-lactam antibiotics: mapping of chromosomal genes. Antimicrob Agents Chemother 1982;22:242–249.

    PubMed  CAS  Google Scholar 

  114. Robillard NJ, Scarpa AL. Genetic and physiological characterization of ciprofloxacin resistance inPseudomonas aeruginosa PAO. Antimicrob Agents Chemother 1988;32: 535–539.

    PubMed  CAS  Google Scholar 

  115. Masuda N, Ohya S. Cross-resistance to meropenem, cephems, and quinolones inPseudomonas aeruginosa. Antimicrob Agents Chemother 1992;36:1847–1851.

    PubMed  CAS  Google Scholar 

  116. Gotoh N, Tsujimoto H., Poole K, Yamagishi J, Nishino T. The outer membrane protein OprM ofPseudomonas aeruginosa is encoded byoprK of the mexA-mexB-oprK multidrug resistance operon. Antimicrob Agents Chemother 1995;39:2567–2569.

    PubMed  CAS  Google Scholar 

  117. Hamzehpour MM, Pechere J, Plesiat P, Kohler T. OprK and OprM define two genetically distinct multidrug efflux systems inPseudomonas aeruginosa. Antimicrob Agents Chemother 1995;39:2392–2396.

    PubMed  CAS  Google Scholar 

  118. Li X-Z, Livermore DM, Nikaido H. Role of efflux pump(s) in intrinsic resistance ofPseudomonas aeruginosa: resistance to tetracycline, chloramphenicol, and norfloxacin. Antimicrob Agents Chemother 1994;38:1732–1741.

    PubMed  CAS  Google Scholar 

  119. Poole K, Tetro K, Zhao Q, Neshat S, Heinrichs E, Bianco N. Expression of the multidrug resistance operonmexA-mexB-oprM inPseudomonas aeruginosa: mexR encodes a regulator of operon expression. Antimicrob Agents Chemother 1996;40:2021–2028.

    PubMed  CAS  Google Scholar 

  120. Hirai K, Suzue S, Irikura T, Iyobe S, Mitsuhashi S. Mutations producing resistance to norfloxacin inPseudomonas aeruginosa. Antimicrob Agents Chemother 1987;31:582–586.

    PubMed  CAS  Google Scholar 

  121. Hosaka M, Gotoh N, Nishino T. Purification of a 54-kilodalton protein (OprJ) produced in NfxB mutants ofPseudomonas auruginosa and production of a monoclonal antibody specific to OprJ. Antimicrob Agents Chemother 1995;39:1731–1735.

    PubMed  CAS  Google Scholar 

  122. Masuda N, Gotoh N, Ohya S, Nishino T. Quantitative correlation between susceptibility and OprJ production in NfxB mutants ofPseudomonas aeruginosa. Antimicrob Agents Chemother 1996;40:909–913.

    PubMed  CAS  Google Scholar 

  123. Okazaki T, Hirai K. Cloning and nucleotide sequence of thePseudomonas aeruginosa nfxB gene, conferring resistance to new quinolones. FEMS Microbiol Lett 1992;97: 197–202.

    CAS  Google Scholar 

  124. Poole K, Gotoh N, Tsujimoto H, Zhao Q, Wasa A, Yamasaki T, et al. Overexpression of themexC-mexD-oprJ efflux operon innfxB-type multidrug-resistant strains ofPseudomonas aeruginosa. Mol Microbiol 1996;21:713–724.

    PubMed  CAS  Google Scholar 

  125. Fukuda H, Hosaka M, Hirai K, Iyobe S. New norfloxacin resistance gene inPseudomonas aeruginosa PAO. Antimicrob Agents Chemother 1990;34:1757–1761.

    PubMed  CAS  Google Scholar 

  126. Fukuda H, Hosaka M, Iyobe S, Gotoh N, Nishino T, Hirai K.nfxC-type quinolone resistance in a clinical isolate ofPseudomonas aeruginosa. Antimicrob Agents Chemother 1995;39:790–792.

    PubMed  CAS  Google Scholar 

  127. Huang H, Hancock REW. Genetic definition of the substrate selectivity of outer membrane porin protein OprD ofPseudomonas aeruginosa. J Bacteriol 1993;175:7793–7800.

    PubMed  CAS  Google Scholar 

  128. Kohler T, Michea-Hamzehpour M, Henze U, Gotoh N, Curty LK, Pechere J-C. Characterization of MexE-MexF-OprN, a positively regulated multidrug efflux system ofPseudomonas aeruginosa. Mol Microbiol 1997;23:345–354.

    PubMed  CAS  Google Scholar 

  129. Piddock LJV, Bellido F, Bains M, Hancock REW. A pleiotropic, posttherapy, enoxacin-resistant mutant ofPseudomonas aeruginosa. Antimicrob Agents Chemother 1992;36:1057–1061.

    PubMed  CAS  Google Scholar 

  130. Young M, Hancock REW. Fluoroquinolone supersusceptibility mediated by outer membrane protein OprH overexpression inPseudomonas aeruginosa: evidence for involvement of a nonporin pathway. Antimicrob Agents Chemother 1992;36:2365–2369.

    PubMed  CAS  Google Scholar 

  131. Ishida H, Fuziwara H, Kaibori Y, Horiuchi T, Sato K, Osada Y. Cloning of multidrug resistance genepqrA fromProteus vulgaris. Antimicrob Agents Chemother 1995;39:453–457.

    PubMed  CAS  Google Scholar 

  132. Ishii H, Sato K, Hoshino K, Sato M, Yamaguchi A, Sawai T, Osada Y. Active efflux of ofloxacin by a highly quinolone-resistant strain ofProteus vulgaris. J Antimicrob Chemother 1991;28:827–836.

    PubMed  CAS  Google Scholar 

  133. Charvalos E, Tselentis Y, Hamzehpour MM, Kohler T, Pechere J-C. Evidence for an efflux pump in multidrug-resistantCampylobacter jejuni. Antimicrob Agents Chemother 1995;39:2019–2022.

    PubMed  CAS  Google Scholar 

  134. Ubukata K, Itoh N-Y, Konno M. Cloning and expression of thenorA gene for fluoroquinolone resistance inStaphylococcus aureus. Antimicrob Agents Chemother 1989;33:1535–1539.

    PubMed  CAS  Google Scholar 

  135. Yoshida H, Bogaki M, Nakamura S, Ubukata K, Konno M. Nucleotide sequence and characterization of theStaphylococcus aureus norA gene, which confers resistance to quinolones. J Bacteriol 1990;172:6942–6949.

    PubMed  CAS  Google Scholar 

  136. Neyfakh AA, Borsch CM, Kaatz GW. Fluoroquinolone resistance protein NorA ofStaphylococcus aureus is a multidrug efflux transporter. Antimicrob Agents Chemother 1993;37:128–129.

    PubMed  CAS  Google Scholar 

  137. Takenouchi T, Tabata F, Iwata Y, Hanzawa H, Sugawara M, Ohya S. Hydrophilicity of quinolones is not an exclusive factor for decreased activity in efflux-mediated resistant mutants ofStaphylococcus aureus. Antimicrob Agents Chemother 1996;40:1835–1842.

    PubMed  CAS  Google Scholar 

  138. Kaatz GW, Seo SM, Ruble CA. Efflux-mediated fluoroquinolone resistance inStaphylococcus aureus. Antimicrob Agents Chemother 1993;37:1086–1094.

    PubMed  CAS  Google Scholar 

  139. Kojima T, Yamagishi J, Oyamada Y, Yoshida H, Hattori H, Inoue M, Nakamura S. Analysis of quinolone resistance genes in a clinical isolate of quinolone-resistant MRSA. Drugs 1995;49(Suppl.2):182–184.

    PubMed  CAS  Google Scholar 

  140. Ng EYW, Trucksis M, Hooper DC. Quinolone resistance mediated bynorA: physiologic characterization and relationship toflqB, a quinolone resistance locus on theStaphylococcus aureus chromosome. Antimicrob Agents Chemother 1994;38:1345–1355.

    PubMed  CAS  Google Scholar 

  141. Kaatz GW, Seo SM. Inducible NorA-mediated multidrug resistance inStaphylococcus aureus. Antimicrob Agents Chemother 1995;39:2650–2655.

    PubMed  CAS  Google Scholar 

  142. Ubukata K. ThenorA gene conferring new quinolone resistance inStaphylococcus epidermidis. Chemotherapy 1991;39:1001–1013 (in Japanese).

    CAS  Google Scholar 

  143. Neyfakh AA. The multidrug efflux transporter ofBacillus subtilis is a structural and functional homolog of theStaphylococcus NorA protein. Antimicrob Agents Chemother 1992;36:484–485.

    PubMed  CAS  Google Scholar 

  144. Takiff HE, Cimino M, Musso MC, Weisbrod T, Martinez R, Delgado MB, et al. Efflux pump of the proton antiporter family confers low-level fluoroquinolone resistance inMycobacterium smegmatis. Proc Natl Acad Sci USA 1996;93:362–366.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

About this article

Cite this article

Nakamura, S. Mechanisms of Quinolone resistance. J Infect Chemother 3, 128–138 (1997). https://doi.org/10.1007/BF02491502

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02491502

Key words

  • mechanism
  • quinolone
  • resistance
  • gyrase
  • topoisomerase IV
  • permeability