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

John P. Pribis, Libertad García-Villada, Yin Zhai, Ohad Lewin-Epstein, Anthony Z. Wang, Jingjing Liu, Jun Xia, Qian Mei, Devon M. Fitzgerald, Julia Bos, Robert H. Austin, Christophe Herman, David Bates, Lilach Hadany, P. J. Hastings, Susan M. Rosenberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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. Bacteria exposed to antibiotic acquire reactive oxygen in a transient “gambler” cell subpopulation that undertakes general stress response-induced mutagenic DNA break repair, evolves resistance to new antibiotics, and is inhibited by an FDA-approved drug that inhibits evolvability.

Original languageEnglish
Pages (from-to)785-800.e7
JournalMolecular Cell
Issue number4
StatePublished - 16 May 2019


FundersFunder number
Israeli Science FundISF 1568/13
National Institutes of HealthR01-GM106373, R35-GM122598, R01-GM088653, R01-GM102679
American Cancer Society132206-PF-18-035-01-DMC, RP160283
National Institute of Diabetes and Digestive and Kidney DiseasesP30DK056338
Cancer Prevention and Research Institute of Texas
John S. Dunn FoundationP30 AI036211, S10 RR024574, P30 CA125123
Baylor College of MedicineCA125123
Israel Science Foundation1568/13
Norges Idrettshøgskole


    • Escherichia coli
    • RpoS (σ) stress response
    • SOS response
    • antibiotic resistance
    • error-prone DNA polymerases
    • evolution
    • fluoroquinolones
    • reactive oxygen species
    • stress-induced mutagenesis


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