Journal article
Quinolones: Action and Resistance Updated
Current topics in medicinal chemistry, Vol.9(11), pp.981-998
08/01/2009
DOI: 10.2174/156802609789630947
PMCID: PMC3182077
PMID: 19747119
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.
Details
- Title: Subtitle
- Quinolones: Action and Resistance Updated
- Creators
- Karl DrlicaHiroshi Hiasa - University of MinnesotaRobert Kerns - University of IowaMuhammad MalikArkady MustaevXilin Zhao
- Resource Type
- Journal article
- Publication Details
- Current topics in medicinal chemistry, Vol.9(11), pp.981-998
- DOI
- 10.2174/156802609789630947
- PMID
- 19747119
- PMCID
- PMC3182077
- NLM abbreviation
- Curr Top Med Chem
- ISSN
- 1568-0266
- eISSN
- 1873-5294
- Publisher
- Bentham Science Publ Ltd
- Number of pages
- 18
- Grant note
- AI063431; AI35357; AI073491; AI068014; GM30717-21 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01AI035257 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) R01GM030717 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS)
- Language
- English
- Date published
- 08/01/2009
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984366035802771
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