title: Joint effects of topoisomerase alterations and plasmid-mediated quinolone-resistant determinants in Salmonella enterica Typhimurium.
abstract: Alterations in topoisomerases and plasmid-mediated quinolone-resistant (PMQR) determinants have been identified as main quinolone-resistant mechanisms in Salmonella enterica Typhimurium. But the joint effects of these mechanisms have not been thoroughly characterized in homologous Salmonella Typhimurium strains. In this study, isogenic topoisomerase mutants were constructed using phage λ Red recombinase system and phage transduction. And the joint effects of topoisomerase mutations (gyrA [S83F], gyrA [S83F, D87N] and parC [S80I]) and PMQR determinants (including qnrB4, qnrS1, aac(6')-Ib-cr, and qepA) were studied in homologous genetic constitutions. Our data showed that mutations in gyrA played a dominant role in fluoroquinolone resistance in Salmonella Typhimurium and have a synergistic effect with other resistant mechanisms. The mutation (S80I) in parC would have no effect in quinolone resistance without gyrA mutations. The joint effect of aac(6')-Ib-cr and topoisomerase mutations were only observed for ciprofloxacin among tested quinolones. Different joint effects between topoisomerase mutations and qepA, qnrB4, or qnrS1 were observed for tested quinolones. Importantly, the acquirement of the PMQR determinants could improve 0- to 32-fold of the host mutant prevention concentration to ciprofloxacin. Our data showed that the acquirement of PMQR determinants could not only improve the host minimal inhibitory concentrations to quinolones but also accelerate the generation of high-level fluoroquinolone-resistant mutants.
authors.affiliation: Department of Microbiology, Chinese PLA General Hospital, Beijing, PR China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Luo
authors.forename: Jingyun
authors.initials: J
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Meng
authors.forename: Yue
authors.initials: Y
authors.lastname: Ma
authors.forename: Changqin
authors.initials: C
authors.lastname: Hu
authors.forename: Shaohong
authors.initials: S
authors.lastname: Jin
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
authors.forename: Shenghui
authors.initials: S
authors.lastname: Cui
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D027081:DNA Gyrase / Q000235:genetics*; D027101:DNA Topoisomerase IV / Q000235:genetics; D024881:Drug Resistance, Bacterial; D008826:Microbial Sensitivity Tests; D009154:Mutation; D015363:Quinolones / Q000494:pharmacology*; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D015363:Quinolones; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase