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

• DOI: 10.1016/j.molcel.2019.02.037
• Publication Date: 2019-04-01T14:36:20Z
• Authors: John P. Pribis; Libertad García-V...; 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
• Keywords: 0301 basic medicine; [SDV]Life Sciences [q-bio]; Sigma Factor; DNA-Directed DNA Polymerase; Gene Expression Regulation, Bacterial; Anti-Bacterial Agents; 3. Good health; [SDV] Life Sciences [q-bio]; 03 medical and health sciences; Ciprofloxacin; Mutagenesis; Drug Resistance, Bacterial; Mutation; Escherichia coli; Reactive Oxygen Species; SOS Response, Genetics; Cell Division; DNA Damage

SUMMARYAntibiotics 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 σSresponse, 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 σSinduction 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.