Language
English
Publication Date
6-23-2023
Journal
Science Advances
DOI
10.1126/sciadv.adg0188
PMID
37352342
PMCID
PMC10289659
PubMedCentral® Posted Date
6-23-2023
PubMedCentral® Full Text Version
Post-print
Abstract
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.
Keywords
Animals, Mice, Pharmaceutical Preparations, Mutagenesis, Mutation, Escherichia coli, Anti-Bacterial Agents, Drug Resistance, Microbial
Published Open-Access
yes
Recommended Citation
Zhai, Yin; Pribis, John P; Dooling, Sean W; et al., "Drugging Evolution of Antibiotic Resistance at a Regulatory Network Hub" (2023). Faculty, Staff and Students Publications. 6324.
https://digitalcommons.library.tmc.edu/baylor_docs/6324