title: β-Lactam antibiotics promote bacterial mutagenesis via an RpoS-mediated reduction in replication fidelity.
abstract: Regardless of their targets and modes of action, subinhibitory concentrations of antibiotics can have an impact on cell physiology and trigger a large variety of cellular responses in different bacterial species. Subinhibitory concentrations of β-lactam antibiotics cause reactive oxygen species production and induce PolIV-dependent mutagenesis in Escherichia coli. Here we show that subinhibitory concentrations of β-lactam antibiotics induce the RpoS regulon. RpoS-regulon induction is required for PolIV-dependent mutagenesis because it diminishes the control of DNA-replication fidelity by depleting MutS in E. coli, Vibrio cholerae and Pseudomonas aeruginosa. We also show that in E. coli, the reduction in mismatch-repair activity is mediated by SdsR, the RpoS-controlled small RNA. In summary, we show that mutagenesis induced by subinhibitory concentrations of antibiotics is a genetically controlled process. Because this mutagenesis can generate mutations conferring antibiotic resistance, it should be taken into consideration for the development of more efficient antimicrobial therapeutic strategies.
authors.affiliation: INSERM U1001, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Gutierrez
authors.forename: L
authors.initials: L
authors.lastname: Laureti
authors.forename: S
authors.initials: S
authors.lastname: Crussard
authors.forename: H
authors.initials: H
authors.lastname: Abida
authors.forename: A
authors.initials: A
authors.lastname: Rodríguez-Rojas
authors.forename: J
authors.initials: J
authors.lastname: Blázquez
authors.forename: Z
authors.initials: Z
authors.lastname: Baharoglu
authors.forename: D
authors.initials: D
authors.lastname: Mazel
authors.forename: F
authors.initials: F
authors.lastname: Darfeuille
authors.forename: J
authors.initials: J
authors.lastname: Vogel
authors.forename: I
authors.initials: I
authors.lastname: Matic
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000235:genetics; D001426:Bacterial Proteins / Q000502:physiology*; D004261:DNA Replication / Q000187:drug effects* / Q000502:physiology; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016296:Mutagenesis; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012808:Sigma Factor / Q000502:physiology*; D014734:Vibrio cholerae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D017382:Reactive Oxygen Species; D012808:Sigma Factor; D047090:beta-Lactams; C069567:sigma factor KatF protein, Bacteria