β-Lactam antibiotics promote bacterial mutagenesis via an RpoS-mediated reduction in replication fidelity

Nat Commun. 2013;4:1610. doi: 10.1038/ncomms2607.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Bacteria / drug effects*
  • Bacteria / genetics
  • Bacterial Proteins / physiology*
  • DNA Replication / drug effects*
  • DNA Replication / physiology
  • Escherichia coli / drug effects
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Mutagenesis*
  • Pseudomonas aeruginosa / drug effects
  • Pseudomonas aeruginosa / genetics
  • Pseudomonas aeruginosa / metabolism
  • Reactive Oxygen Species / metabolism
  • Sigma Factor / physiology*
  • Vibrio cholerae / drug effects
  • Vibrio cholerae / genetics
  • Vibrio cholerae / metabolism
  • beta-Lactams / pharmacology*

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Reactive Oxygen Species
  • Sigma Factor
  • beta-Lactams
  • sigma factor KatF protein, Bacteria