title: Clinically relevant mutant DNA gyrase alters supercoiling, changes the transcriptome, and confers multidrug resistance.
abstract: Bacterial DNA is maintained in a supercoiled state controlled by the action of topoisomerases. Alterations in supercoiling affect fundamental cellular processes, including transcription. Here, we show that substitution at position 87 of GyrA of Salmonella influences sensitivity to antibiotics, including nonquinolone drugs, alters global supercoiling, and results in an altered transcriptome with increased expression of stress response pathways. Decreased susceptibility to multiple antibiotics seen with a GyrA Asp87Gly mutant was not a result of increased efflux activity or reduced reactive-oxygen production. These data show that a frequently observed and clinically relevant substitution within GyrA results in altered expression of numerous genes, including those important in bacterial survival of stress, suggesting that GyrA mutants may have a selective advantage under specific conditions. Our findings help contextualize the high rate of quinolone resistance in pathogenic strains of bacteria and may partly explain why such mutant strains are evolutionarily successful.
  
  
  OBJECTIVE
  Fluoroquinolones are a powerful group of antibiotics that target bacterial enzymes involved in helping bacteria maintain the conformation of their chromosome. Mutations in the target enzymes allow bacteria to become resistant to these antibiotics, and fluoroquinolone resistance is common. We show here that these mutations also provide protection against a broad range of other antimicrobials by triggering a defensive stress response in the cell. This work suggests that fluoroquinolone resistance mutations may be beneficial under a range of conditions.
authors.affiliation: Antimicrobial Agents Research Group, School of Immunity and Infection, Institute of Microbiology and Infection, The University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Webber
authors.forename: Vito
authors.initials: V
authors.lastname: Ricci
authors.forename: Rebekah
authors.initials: R
authors.lastname: Whitehead
authors.forename: Meha
authors.initials: M
authors.lastname: Patel
authors.forename: Maria
authors.initials: M
authors.lastname: Fookes
authors.forename: Alasdair
authors.initials: A
authors.lastname: Ivens
authors.forename: Laura J V
authors.initials: LJ
authors.lastname: Piddock
mesh_terms: D019943:Amino Acid Substitution; D000900:Anti-Bacterial Agents / Q000378:metabolism; D027081:DNA Gyrase / Q000235:genetics* / Q000378:metabolism*; D004278:DNA, Superhelical / Q000378:metabolism*; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D012486:Salmonella typhimurium / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D012641:Selection, Genetic; D013312:Stress, Physiological; D059467:Transcriptome
chemical_list: D000900:Anti-Bacterial Agents; D004278:DNA, Superhelical; D050505:Mutant Proteins; D027081:DNA Gyrase