title: Quinolones: action and resistance updated.
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.
authors.affiliation: Public Health Research Institute, New Jersey Medical School, UMDNJ, 225 Warren Street, Newark, NJ 07103, USA. drlicaka@umdnj.edu
authors.forename: Karl
authors.initials: K
authors.lastname: Drlica
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hiasa
authors.forename: Robert
authors.initials: R
authors.lastname: Kerns
authors.forename: Muhammad
authors.initials: M
authors.lastname: Malik
authors.forename: Arkady
authors.initials: A
authors.lastname: Mustaev
authors.forename: Xilin
authors.initials: X
authors.lastname: Zhao
mesh_terms: D001419:Bacteria / Q000187:drug effects; D018360:Crystallography, X-Ray; D004352:Drug Resistance, Microbial / Q000235:genetics; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D015363:Quinolones