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© Melanie Blokesch, EPFL
Flagellated Vibrio cholerae
Publication : Molecular cell

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

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Molecular cell - 16 May 2019

Pribis JP, García-Villada L, Zhai Y, Lewin-Epstein O, Wang AZ, Liu J, Xia J, Mei Q, Fitzgerald DM, Bos J, Austin RH, Herman C, Bates D, Hadany L, Hastings PJ, Rosenberg SM,

Link to Pubmed [PMID] – 30948267

Link to DOI – S1097-2765(19)30148-010.1016/j.molcel.2019.02.037

Mol Cell 2019 05; 74(4): 785-800.e7

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.

https://pubmed.ncbi.nlm.nih.gov/30948267