Mechanisms of Fluoroquinolone Action and Resistance

  • Karl Drlica
Conference paper

Abstract

Intracellular fluoroquinolone action involves two steps. First, drug-topoisomerase-DNA complexes form in which the DNA is broken. These complexes reversibly block DNA replication and bacterial growth. Second, lethal DNA breaks are released from the complexes. Inhibitors of protein synthesis, such as chloramphenicol, block cell death and the release of DNA breaks from complexes trapped by oxolinic acid, a first generation quinolone. However, they only partially protect cells from the lethal action of fluoroquinolones, suggesting that these compounds act by the chloramphenicol-sensitive pathway and by a second pathway. Resistance to fluoroquinolones arises step-wise from mutations in the two intracellular targets, DNA gyrase and DNA topoisomerase IV. Addition of a methoxy group to N1-cyclopropyl fluoroquinolones improves bacteriostatic and bactericidal action, especially against first-step, resistant mutants. Consequently, C-8-methoxy derivatives restrict the selection of resistance by bacterial populations, a feature that has been shown for several bacterial species including clinical MDR isolates ofMycobacterium tuberculosis. Since minimum inhibitory concentration (MIC) against wild-type cells fails to accurately predict attack of resistant mutants or selection of resistance, a new parameter called mutant prevention concentration (MPC) is proposed as an additional measure of quinolone potency.

Keywords

Tuberculosis Sedimentation Compaction Chloramphenicol Topo 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2000

Authors and Affiliations

  • Karl Drlica

There are no affiliations available

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