, Volume 58, Supplement 2, pp 6–10 | Cite as

Mode of Action of Fluoroquinolones

  • David C. HooperEmail author
Oral Presentations Review Article


The mode of action of quinolones involves interactions with both DNA gyrase, the originally recognised drug target, and topoisomerase IV, a related type II topoisomerase. In a given bacterium these 2 enzymes often differ in their relative sensitivities to many quinolones, and commonly DNA gyrase is more sensitive in Gram-negative bacteria and topoisomerase IV more sensitive in Gram-positive bacteria. Usually the more sensitive enzyme represents the primary drug target determined by genetic tests, but poorly understood exceptions have been documented.

The formation of the ternary complex of quinolone, DNA, and either DNA gyrase or topoisomerase IV occurs through interactions in which quinolone binding appears to induce changes in both DNA and the topoisomerase that occur separately from the DNA cleavage that is the hallmark of quinolone action. X-ray crystallographic studies of a fragment of the gyrase A subunit, as well as of yeast topoisomerase IV, which has homology to the subunits of both DNA gyrase and topoisomerase IV, have revealed domains that are likely to constitute quinolone binding sites, but no topoisomerase crystal structures that include DNA and quinolone have been reported to date.

Inhibition of DNA synthesis by quinolones requires the targeted topoisomerase to have DNA cleavage capability, and collisions of the replication fork with reversible quinolone-DNA-topoisomerase complexes convert them to an irreversible form. However, the molecular factors that subsequently generate DNA double-strand breaks from the irreversible complexes and that probably initiate cell death have yet to be defined.


Quinolone Antimicrob Agent Sparfloxacin Quinolone Resistance Clinafloxacin 
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  1. 1.
    Hane MW, Wood TH. Escherichia coli K-12 mutants resistant to nalidixic acid: genetic mapping and dominance studies. J Bacteriol 1969; 99: 238–41PubMedGoogle Scholar
  2. 2.
    Yoshida H, Kojima T, Yamagishi J, et al. Quinolone-resistant mutations of the gyrA gene of Escherichia coli. Mol Gen Genet 1988; 211: 1–7PubMedCrossRefGoogle Scholar
  3. 3.
    Nakamura S, Nakamura M, Kojima T, et al. gyrA and gyrB mutations in quinolone-resistant strains of Escherichia coli. Antimicrob Agents Chemother 1989; 33: 254–5PubMedCrossRefGoogle Scholar
  4. 4.
    Kato J, Nishimura Y, Imamura R, et al. New topoisomerase essential for chromosome segregation in E. coli. Cell 1990; 63: 393–404PubMedCrossRefGoogle Scholar
  5. 5.
    Hoshino K, Kitamura A, Morrissey I, et al. Comparison of inhibition of Escherichia coli topoisomerase IV by quinolones with DNA gyrase inhibition. Antimicrob Agents Chemother 1994; 38: 2623–7PubMedCrossRefGoogle Scholar
  6. 6.
    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; 39: 1554–8PubMedCrossRefGoogle Scholar
  7. 7.
    Ferrero L, Cameron B, Manse B, et al. Cloning and primary structure of Staphylococcus aureus DNA topoisomerase IV: a primary target of fluoroquinolones. Mol Microbiol 1994; 13: 641–53PubMedCrossRefGoogle Scholar
  8. 8.
    Ng EY, Trucksis M, Hooper DC. Quinolone resistance mutations in topoisomerase IV: relationship of the flqA locus and genetic evidence that topoisomerase IV is the primary target and DNA gyrase the secondary target of fluoroquinolones in Staphylococcus aureus. Antimicrob Agents Chemother 1996; 40: 1881–8PubMedGoogle Scholar
  9. 9.
    Khodursky AB, Zechiedrich EL, Cozzarelli NR. Topoisomerase IV is a target of quinolones in Escherichia coli. Proc Natl Acad Sci USA 1995; 92: 11801–5PubMedCrossRefGoogle Scholar
  10. 10.
    Breines DM, Ouabdesselam S, Ng EY, et al. Quinolone resistance locus nfxD of Escherichia coli is a mutant allele of parE gene encoding a subunit of topoisomerase IV Antimicrob Agents Chemother 1997; 41: 175–9Google Scholar
  11. 11.
    Soussy CJ, Wolfson JS, Ng EY, et al. Limitations of plasmid complementation test for determination of quinolone resistance due to changes in the gyrase A protein and identification of conditional quinolone resistance locus. Antimicrob Agents Chemother 1993; 37: 2588–92PubMedCrossRefGoogle Scholar
  12. 12.
    Hooper DC. Mechanisms of quinolone resistance. Drug Resistance Updates 1999; 2: 38–55PubMedCrossRefGoogle Scholar
  13. 13.
    Fournier B, Hooper DC. Mutations in topoisomerase IV and DNA gyrase of Staphylococcus aureus: Novel pleiotropic effects on quinolone and coumarin activity. Antimicrob Agents Chemother 1998; 42: 121–8PubMedCrossRefGoogle Scholar
  14. 14.
    Blanche F, Cameron B, Bernard FX, et al. Differential behaviors of Staphylococcus aureus and Escherichia coli type II DNA topoisomerases. Antimicrob Agents Chemother 1996; 40: 2714–20PubMedGoogle Scholar
  15. 15.
    Pan XS, Fisher LM. Targeting of DNA gyrase in Streptococcus pneumoniae by sparfloxacin: selective targeting of gyrase or topoisomerase IV by quinolones. Antimicrob Agents Chemother 1997; 41: 471–4PubMedGoogle Scholar
  16. 16.
    Pan XS, Fisher LM. DNA gyrase and topoisomerase IV are dual targets of clinafloxacin action in Streptococcus pneumoniae. Antimicrob Agents Chemother 1998; 42: 2810–6PubMedGoogle Scholar
  17. 17.
    Pan XS, Fisher LM. Streptococcus pneumoniae DNA gyrase and topoisomerase IV: overexpression, purification, and differential inhibition by fluoro quinolones. Antimicrob Agents Chemother 1999; 43: 1129–36PubMedGoogle Scholar
  18. 18.
    Morrissey I, George JT. The unique equipotency of sitafloxacin against topoisomerase IV and DNA gyrase from Streptococcus pneumoniae. Abstract from the 6th International Symposium on New Quinolones; 1998 Nov 15–17: Denver, USAGoogle Scholar
  19. 19.
    Cole ST, Brosch R, Parkhill J, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998; 393: 537–44PubMedCrossRefGoogle Scholar
  20. 20.
    Fraser CM, Norris SJ, Weinstock GM, et al. Complete genome sequence of Treponema pallidum, the syphilis spirochete. Science 1998; 281: 375–88PubMedCrossRefGoogle Scholar
  21. 21.
    Tomb JF, White O, Kerlavage AR, et al. The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature 1997; 388: 539–47PubMedCrossRefGoogle Scholar
  22. 22.
    Berger JM, Gamblin SJ, Harrison SC, et al. Structure and mechanism of DNA topoisomerase II. Nature 1996; 379: 225–32PubMedCrossRefGoogle Scholar
  23. 23.
    Cabrai JH, Jackson AP, Smith CV, et al. Crystal structure of the breakage-reunion domain of DNA gyrase. Nature 1997; 388: 903–6CrossRefGoogle Scholar
  24. 24.
    Lewis RJ, Singh OM, Smith CV, et al. Crystallization of inhibitor complexes of an N-terminal 24 kDa fragment of the DNA gyrase B protein. J Mol Biol 1994; 241: 128–30PubMedCrossRefGoogle Scholar
  25. 25.
    Berger JM. Type II DNA topoisomerases. Curr Opin Struct Biol 1998; 8: 26–32PubMedCrossRefGoogle Scholar
  26. 26.
    Willmott CJ, 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: 126–7PubMedCrossRefGoogle Scholar
  27. 27.
    Fass D, Bogden CE, Berger JM. Quaternary changes in topoisomerase II may direct orthogonal movement of two DNA strands. Nat Struct Biol 1999; 6: 322–6PubMedCrossRefGoogle Scholar
  28. 28.
    Shen LL, Kohlbrenner WE, Weigl D, et al. Mechanism of quinolone inhibition of DNA gyrase. Appearance of unique norfloxacin binding sites in enzyme-DNA complexes. J Biol Chem 1989; 264: 2973–8Google Scholar
  29. 29.
    Marians KJ, Hiasa H. Mechanism of quinolone action — a drug-induced structural perturbation of the DNA precedes strand cleavage by topoisomerase IV. J Biol Chem 1997; 272: 9401–9PubMedCrossRefGoogle Scholar
  30. 30.
    Critchlow SE, Maxwell A. DNA cleavage is not required for the binding of quinolone drugs to the DNA gyrase — DNA complex. Biochemistry 1996; 35: 7387–93PubMedCrossRefGoogle Scholar
  31. 31.
    Kampranis SC, Maxwell A. Conformational changes in DNA gyrase revealed by limited proteolysis. J Biol Chem 1998; 273: 22606–14PubMedCrossRefGoogle Scholar
  32. 32.
    Kampranis SC, Maxwell A. The DNA gyrase-quinolone complex — ATP hydrolysis and the mechanism of DNA cleavage. J Biol Chem 1998; 273: 22615–26PubMedCrossRefGoogle Scholar
  33. 33.
    Scheirer KE, Higgins NP. The DNA cleavage reaction of DNA gyrase — comparison of stable ternary complexes formed with enoxacin and CcdB protein. J Biol Chem 1997; 272: 27202–9PubMedCrossRefGoogle Scholar
  34. 34.
    Khodursky AB, Cozzarelli NR. The mechanism of inhibition of topoisomerase IV by quinolone antibacterials. J Biol Chem 1998; 273: 27668–77PubMedCrossRefGoogle Scholar
  35. 35.
    Hiasa H, Yousef DO, Marians KJ. DNA strand cleavage is required for replication fork arrest by a frozen topoisomerase-quinolone-DNA ternary complex. J Biol Chem 1996; 271: 26424–9PubMedCrossRefGoogle Scholar
  36. 36.
    Drlica K, Engle EC, Manes SH. DNA gyrase on the bacterial chromosome: possibility of two levels of action. Proc Natl Acad Sci USA 1980; 77: 6879–83PubMedCrossRefGoogle Scholar
  37. 37.
    Huang WM, Libbey JL, Van der Hoeven P, et al. Bipolar localization of Bacillus subtilis topoisomerase IV, an enzyme required for chromosome segregation. Proc Natl Acad Sci USA 1998; 95: 4652–7PubMedCrossRefGoogle Scholar
  38. 38.
    Willmott CJ, Critchlow SE, Eperon IC, et al. The complex of DNA gyrase and quinolone drugs with DNA forms a barrier to transcription by RNA polymerase. J Mol Biol 1994; 242: 351–63PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1999

Authors and Affiliations

  1. 1.Division of Infectious DiseasesMassachusetts General Hospital, Harvard Medical SchoolBostonUSA

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