Dual targeting of topoisomerase IV and gyrase to reduce mutant selection: direct testing of the paradigm by using WCK-1734, a new fluoroquinolone, and ciprofloxacin.

ABSTRACT: Quinolones that act equally against DNA gyrase and topoisomerase IV are a desirable modality to decrease the selection of resistant strains. We first determined by genetic and biochemical studies in Staphylococcus aureus that the primary target enzyme of WCK-1734, a new quinolone, was DNA gyrase. A single mutation in gyrase, but not topoisomerase IV, caused a two- to fourfold increase in the MIC. Studies with purified topoisomerase IV and gyrase from S. aureus also showed that gyrase was more sensitive than topoisomerase IV to WCK-1734 (50% inhibitory concentration, 1.25 and 2.5 to 5.0 microg/ml, respectively; 50% stimulation of cleavage complex formation, 0.62 and 2.5 to 5.0 microg/ml, respectively). To test the effect of balanced activity of quinolones against the two target enzymes, we

SUBMITTER: Strahilevitz J 

PROVIDER: S-EPMC1087631 | biostudies-literature | 2005 May

REPOSITORIES: biostudies-literature