Quinolones: Action and Resistance Updated

Author(s): Karl Drlica , Hiroshi Hiasa , Robert Kerns , Muhammad Malik , Arkady Mustaev , Xilin Zhao .

Journal Name: Current Topics in Medicinal Chemistry

Volume 9 , Issue 11 , 2009

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Abstract:

The quinolones trap DNA gyrase and DNA topoisomerase IV on DNA as complexes in which the DNA is broken but constrained by protein. Early studies suggested that drug binding occurs largely along helix-4 of the GyrA (gyrase) and ParC (topoisomerase IV) proteins. However, recent X-ray crystallography shows drug intercalating between the -1 and +1 nucleotides of cut DNA, with only one end of the drug extending to helix-4. These two models may reflect distinct structural steps in complex formation. A consequence of drug-enzyme-DNA complex formation is reversible inhibition of DNA replication; cell death arises from subsequent events in which bacterial chromosomes are fragmented through two poorly understood pathways. In one pathway, chromosome fragmentation stimulates excessive accumulation of highly toxic reactive oxygen species that are responsible for cell death. Quinolone resistance arises stepwise through selective amplification of mutants when drug concentrations are above the MIC and below the MPC, as observed with static agar plate assays, dynamic in vitro systems, and experimental infection of rabbits. The gap between MIC and MPC can be narrowed by compound design that should restrict the emergence of resistance. Resistance is likely to become increasingly important, since three types of plasmid-borne resistance have been reported.

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Article Details

VOLUME: 9
ISSUE: 11
Year: 2009
Page: [981 - 998]
Pages: 18
DOI: 10.2174/156802609789630947
Price: $58

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