Drugging evolution of antibiotic resistance at a regulatory network hub

Sci Adv. 2023 Jun 23;9(25):eadg0188. doi: 10.1126/sciadv.adg0188. Epub 2023 Jun 23.


Evolution of antibiotic resistance is a world health crisis, fueled by new mutations. Drugs to slow mutagenesis could, as cotherapies, prolong the shelf-life of antibiotics, yet evolution-slowing drugs and drug targets have been underexplored and ineffective. Here, we used a network-based strategy to identify drugs that block hubs of fluoroquinolone antibiotic-induced mutagenesis. We identify a U.S. Food and Drug Administration- and European Medicines Agency-approved drug, dequalinium chloride (DEQ), that inhibits activation of the Escherichia coli general stress response, which promotes ciprofloxacin-induced (stress-induced) mutagenic DNA break repair. We uncover the step in the pathway inhibited: activation of the upstream "stringent" starvation stress response, and find that DEQ slows evolution without favoring proliferation of DEQ-resistant mutants. Furthermore, we demonstrate stress-induced mutagenesis during mouse infections and its inhibition by DEQ. Our work provides a proof-of-concept strategy for drugs to slow evolution in bacteria and generally.

MeSH terms

  • Animals
  • Anti-Bacterial Agents* / metabolism
  • Anti-Bacterial Agents* / pharmacology
  • Drug Resistance, Microbial / genetics
  • Escherichia coli* / metabolism
  • Mice
  • Mutagenesis
  • Mutation
  • Pharmaceutical Preparations / metabolism


  • Pharmaceutical Preparations
  • Anti-Bacterial Agents