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Quinolones inhibit DNA religation mediated by Staphylococcus aureus topoisomerase IV. Changes in drug mechanism

V E Anderson1, R P Zaniewski, F S Kaczmarek

  • 1Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.

The Journal of Biological Chemistry
|December 10, 1999
PubMed

Insights

Ciprofloxacin enhances DNA cleavage by Staphylococcus aureus topoisomerase IV, significantly inhibiting DNA religation. This suggests subtle drug-enzyme interactions, not binding site differences, explain quinolone mechanism variations across species.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Biochemistry

Background:

  • Quinolones are potent oral antibacterials targeting prokaryotic type II topoisomerases.
  • Topoisomerase IV is a key target for quinolones in Gram-positive bacteria, but drug interactions are not fully understood.

Purpose of the Study:

  • To investigate the effects of ciprofloxacin on DNA cleavage and religation by Staphylococcus aureus topoisomerase IV.

Main Methods:

  • Characterization of DNA cleavage and religation reactions mediated by purified S. aureus topoisomerase IV in the presence of varying ciprofloxacin concentrations.

Main Results:

  • Ciprofloxacin significantly increased DNA scission by S. aureus topoisomerase IV in a dose-dependent manner.
  • Ciprofloxacin dramatically inhibited the DNA religation activity of S. aureus topoisomerase IV.

Conclusions:

  • The mechanism of quinolone action may differ between bacterial and eukaryotic type II topoisomerases, with religation inhibition being a key factor in bacteria.
  • Subtle alterations in drug orientation within the enzyme-drug-DNA complex, rather than changes in the binding site, likely explain these mechanistic differences.

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