title: Inhibition of mutation and combating the evolution of antibiotic resistance.
abstract: The emergence of drug-resistant bacteria poses a serious threat to human health. In the case of several antibiotics, including those of the quinolone and rifamycin classes, bacteria rapidly acquire resistance through mutation of chromosomal genes during therapy. In this work, we show that preventing induction of the SOS response by interfering with the activity of the protease LexA renders pathogenic Escherichia coli unable to evolve resistance in vivo to ciprofloxacin or rifampicin, important quinolone and rifamycin antibiotics. We show in vitro that LexA cleavage is induced during RecBC-mediated repair of ciprofloxacin-mediated DNA damage and that this results in the derepression of the SOS-regulated polymerases Pol II, Pol IV and Pol V, which collaborate to induce resistance-conferring mutations. Our findings indicate that the inhibition of mutation could serve as a novel therapeutic strategy to combat the evolution of antibiotic resistance.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Cirz
authors.forename: Jodie K
authors.initials: JK
authors.lastname: Chin
authors.forename: David R
authors.initials: DR
authors.lastname: Andes
authors.forename: Valérie
authors.initials: V
authors.lastname: de Crécy-Lagard
authors.forename: William A
authors.initials: WA
authors.lastname: Craig
authors.forename: Floyd E
authors.initials: FE
authors.lastname: Romesberg
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D002939:Ciprofloxacin / Q000494:pharmacology; D004249:DNA Damage; D004269:DNA, Bacterial / Q000235:genetics; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000235:genetics*; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D004927:Escherichia coli Infections; D019143:Evolution, Molecular; D051379:Mice; D008826:Microbial Sensitivity Tests; D009154:Mutation; D012097:Repressor Proteins / Q000235:genetics; D012293:Rifampin / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000235:genetics; D000099160:LexA Repressor Protein
chemical_list: D001426:Bacterial Proteins; D002939:Ciprofloxacin; D004269:DNA, Bacterial; D012097:Repressor Proteins; D012293:Rifampin; D012697:Serine Endopeptidases; D000099160:LexA Repressor Protein