TY - JOUR T1 - Gamblers: an Antibiotic-induced Evolvable Cell Subpopulation Differentiated by Reactive-oxygen-induced General Stress Response JF - bioRxiv DO - 10.1101/493015 SP - 493015 AU - John P Pribis AU - Libertad García-Villada AU - Yin Zhai AU - Ohad Lewin-Epstein AU - Anthony Wang AU - Jingjing Liu AU - Jun Xia AU - Qian Mei AU - Devon M. Fitzgerald AU - Julia Bos AU - Robert Austin AU - Christophe Herman AU - David Bates AU - Lilach Hadany AU - P.J. Hastings AU - Susan M Rosenberg Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/12/11/493015.abstract N2 - 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. ER -