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bioRxiv · 10.1101/493015

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

Pribis, J. P.·Garcia-Villada, L.·Zhai, Y.·Lewin-Epstein, O.·Wang, A.·Liu, J.·Xia, J.·Mei, Q.·Fitzgerald, D. M.·Bos, J.·Austin, R.·Herman, C.·Bates, D.·Hadany, L.·Hastings, P. J.·Rosenberg, S. M.
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Abstract

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 ({sigma}S) 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 {sigma}S response, allowing mutagenesis during DNA-break repair. When sorted, this small {sigma}S-response-\"on\" subpopulation produces most antibiotic cross-resistant mutants. An FDA-approved drug prevents {sigma}S 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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Pribis, J. P., Garcia-Villada, L., Zhai, Y., Lewin-Epstein, O., Wang, A., Liu, J., Xia, J., Mei, Q., Fitzgerald, D. M., Bos, J., Austin, R., Herman, C., Bates, D., Hadany, L., Hastings, P. J., Rosenberg, S. M.. 2018-12-11. Gamblers: an Antibiotic-induced Evolvable Cell Subpopulation Differentiated by Reactive-oxygen-induced General Stress Response. https://doi.org/10.1101/493015

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