title: Impact of fluoroquinolone resistance mutations on gonococcal fitness and in vivo selection for compensatory mutations.
abstract: BACKGROUND
  Quinolone-resistant Neisseria gonorrhoeae (QRNG) arise from mutations in gyrA (intermediate resistance) or gyrA and parC (resistance). Here we tested the consequence of commonly isolated gyrA(91/95) and parC86 mutations on gonococcal fitness.
  
  
  METHODS
  Mutant gyrA(91/95) and parC86 alleles were introduced into wild-type gonococci or an isogenic mutant that is resistant to macrolides due to an mtrR(-79) mutation. Wild-type and mutant bacteria were compared for growth in vitro and in competitive murine infection.
  
  
  RESULTS
  In vitro growth was reduced with increasing numbers of mutations. Interestingly, the gyrA(91/95) mutation conferred an in vivo fitness benefit to wild-type and mtrR(-79) mutant gonococci. The gyrA(91/95), parC86 mutant, in contrast, showed a slight fitness defect in vivo, and the gyrA(91/95), parC86, mtrR(-79) mutant was markedly less fit relative to the parent strains. A ciprofloxacin-resistant (Cip(R)) mutant was selected during infection with the gyrA(91/95), parC86, mtrR(-79) mutant in which the mtrR(-79) mutation was repaired and the gyrA(91) mutation was altered. This in vivo-selected mutant grew as well as the wild-type strain in vitro.
  
  
  CONCLUSIONS
  gyrA(91/95) mutations may contribute to the spread of QRNG. Further acquisition of a parC86 mutation abrogates this fitness advantage; however, compensatory mutations can occur that restore in vivo fitness and maintain Cip(R).
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Anjali N
authors.initials: AN
authors.lastname: Kunz
authors.forename: Afrin A
authors.initials: AA
authors.lastname: Begum
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: D'Ambrozio
authors.forename: James M
authors.initials: JM
authors.lastname: Robinson
authors.forename: William M
authors.initials: WM
authors.lastname: Shafer
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Bash
authors.forename: Ann E
authors.initials: AE
authors.lastname: Jerse
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D027081:DNA Gyrase / Q000235:genetics; D027101:DNA Topoisomerase IV / Q000235:genetics; D024881:Drug Resistance, Bacterial; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology*; D006069:Gonorrhea / Q000382:microbiology / Q000473:pathology; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009344:Neisseria gonorrhoeae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D014774:Virulence
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D018942:Macrolides; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase