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Gamblers: an Antibiotic-induced Evolvable Cell Subpopulation Differentiated by Reactive-oxygen-induced General Stress Response

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

Posted 11 Dec 2018
bioRxiv DOI: 10.1101/493015 (published DOI: 10.1016/j.molcel.2019.02.037)

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 that cause drug resistance by triggering differentiation of a mutant-generating cell subpopulation, using reactive oxygen species (ROS) to signal the sigma-S (σS) general-stress response. Cipro-generated DNA breaks activate the SOS DNA-damage response and error-prone DNA polymerases in all cells. However, mutagenesis is restricted to a cell subpopulation in which electron transfer and SOS induce ROS, which activate the σS response, allowing mutagenesis during DNA-break repair. When sorted, this small σS-response-'on' subpopulation produces most antibiotic cross-resistant mutants. An FDA-approved drug prevents σS induction specifically inhibiting antibiotic-promoted mutagenesis. Furthermore, SOS-inhibited cell division, causing multi-chromosome cells, is required for 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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