title: Substitutions of amino acids in alpha-helix-4 of gyrase A confer fluoroquinolone resistance on Clostridium perfringens.
abstract: DNA gyrase, an essential enzyme that regulates DNA topology in bacteria, is the target of fluoroquinolones. Three fluoroquinolone-resistant mutants derived from one strain of Clostridium perfringens had amino acid substitutions of glycine 81 to cysteine, aspartic acid 87 to tyrosine, or both, in alpha-helix-4 of gyrase A. The gyrase mutations affected the growth kinetics of mutants differently when the mutants were exposed to increasing concentrations of gatifloxacin and ciprofloxacin. Fluoroquinolone concentration-dependent effects observed during growth in the exponential and stationary phases depended on the presence of particular gyrA mutations. Introduction of a wild-type gyrA gene into the mutants enhanced their susceptibility to fluoroquinolones and decreased their growth rates proportional to increases in fluoroquinolone concentrations. Amino acid substitutions in alpha-helix-4 of gyrase A protected C. perfringens from fluoroquinolones, and a strain with two substitutions was the most resistant.
authors.affiliation: Division of Microbiology, National Center for Toxicological Research, FDA, Jefferson, AR 72079, USA. Fatemeh.rafii@fda.hhs.gov
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Rafii
authors.forename: Miseon
authors.initials: M
authors.lastname: Park
mesh_terms: D019943:Amino Acid Substitution / Q000187:drug effects / Q000235:genetics; D000890:Anti-Infective Agents / Q000494:pharmacology*; D003016:Clostridium perfringens / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D027081:DNA Gyrase / Q000235:genetics / Q000502:physiology*; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D024841:Fluoroquinolones / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship
chemical_list: D000890:Anti-Infective Agents; D004269:DNA, Bacterial; D024841:Fluoroquinolones; D027081:DNA Gyrase