Journal
MOLECULAR CELL
Volume 74, Issue 4, Pages 785-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2019.02.037
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Funding
- NIH [R35-GM122598, R01-GM088653, R01-GM102679, R01-GM106373]
- Israeli Science Fund [ISF 1568/13]
- Baylor College of Medicine (BCM) Integrated Microscopy Core - NIH [DK56338, CA125123]
- Dan L. Duncan Comprehensive Cancer Center
- Cancer Prevention and Research Institute of Texas BCM Cancer Training Program
- American Cancer Society [RP160283, 132206-PF-18-035-01-DMC]
- John S. Dunn Gulf Coast Consortium for Chemical Genomics
- BCM Cytometry and Cell Sorting Core [NIH P30 AI036211, P30 CA125123, S10 RR024574]
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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 (sigma(s)) general-stress response, which allows mutagenic DNA-break repair. When sorted, this small sigma(s)-response-on subpopulation produces most antibiotic cross-resistant mutants. A U.S. Food and Drug Administration (FDA)-approved drug prevents sigma(s) 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.
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