Gamblers: An Antibiotic-Induced Evolvable Cell Subpopulation Differentiated by Reactive-Oxygen-Induced General Stress Response

Mol Cell. 2019 May 16;74(4):785-800.e7. doi: 10.1016/j.molcel.2019.02.037. Epub 2019 Apr 1.


Antibiotics can induce mutations that cause antibiotic resistance. Yet, despite their importance, mechanisms of antibiotic-promoted mutagenesis remain elusive. We report that the fluoroquinolone antibiotic ciprofloxacin (cipro) induces mutations by triggering transient differentiation of a mutant-generating cell subpopulation, using reactive oxygen species (ROS). Cipro-induced DNA breaks activate the Escherichia coli SOS DNA-damage response and error-prone DNA polymerases in all cells. However, mutagenesis is limited to a cell subpopulation in which electron transfer together with SOS induce ROS, which activate the sigma-S (σS) general-stress response, which allows mutagenic DNA-break repair. When sorted, this small σS-response-"on" subpopulation produces most antibiotic cross-resistant mutants. A U.S. Food and Drug Administration (FDA)-approved drug prevents σS induction, specifically inhibiting antibiotic-promoted mutagenesis. Further, SOS-inhibited cell division, which causes multi-chromosome cells, promotes mutagenesis. The data support a model in which within-cell chromosome cooperation together with development of a "gambler" cell subpopulation promote resistance evolution without risking most cells.

Keywords: Escherichia coli; RpoS (σ(S)) stress response; SOS response; antibiotic resistance; error-prone DNA polymerases; evolution; fluoroquinolones; reactive oxygen species; stress-induced mutagenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / adverse effects*
  • Cell Division / drug effects
  • Ciprofloxacin / adverse effects
  • DNA Damage / drug effects
  • DNA-Directed DNA Polymerase / genetics
  • Drug Resistance, Bacterial / drug effects
  • Drug Resistance, Bacterial / genetics*
  • Escherichia coli / drug effects
  • Escherichia coli / genetics*
  • Escherichia coli / pathogenicity
  • Gene Expression Regulation, Bacterial / drug effects
  • Mutagenesis / drug effects
  • Mutagenesis / genetics*
  • Mutation
  • Reactive Oxygen Species / metabolism
  • SOS Response, Genetics / drug effects
  • Sigma Factor / genetics


  • Anti-Bacterial Agents
  • Reactive Oxygen Species
  • Sigma Factor
  • Ciprofloxacin
  • DNA-Directed DNA Polymerase