TY - JOUR
T1 - Gamblers
T2 - An Antibiotic-Induced Evolvable Cell Subpopulation Differentiated by Reactive-Oxygen-Induced General Stress Response
AU - Pribis, John P.
AU - García-Villada, Libertad
AU - Zhai, Yin
AU - Lewin-Epstein, Ohad
AU - Wang, Anthony Z.
AU - Liu, Jingjing
AU - Xia, Jun
AU - Mei, Qian
AU - Fitzgerald, Devon M.
AU - Bos, Julia
AU - Austin, Robert H.
AU - Herman, Christophe
AU - Bates, David
AU - Hadany, Lilach
AU - Hastings, P. J.
AU - Rosenberg, Susan M.
N1 - Funding Information:
We thank S. Gottesman, J. Imlay, I. Matic, and L. Zechiedrich for E. coli strains, N. Majdalani and S. Kozmin for advice, S. Henikoff for helpful conversation, K.M. Miller and Meng Wang for improving the manuscript, and appreciate the expert assistance of J.M. Sederstrom. This work was supported by NIH (R35-GM122598 to S.M.R. R01-GM088653 to C.H. R01-GM102679 to D.B. and R01-GM106373 to P.J.H.), the Israeli Science Fund (ISF 1568/13 to L.H.), Baylor College of Medicine (BCM) Integrated Microscopy Core funded by NIH (DK56338 and CA125123) and the Dan L. Duncan Comprehensive Cancer Center, postdoctoral fellowships from the Cancer Prevention and Research Institute of Texas BCM Cancer Training Program, and the American Cancer Society (RP160283 and 132206-PF-18-035-01-DMC to D.M.F.), the John S. Dunn Gulf Coast Consortium for Chemical Genomics, and the BCM Cytometry and Cell Sorting Core (NIH P30 AI036211, P30 CA125123, and S10 RR024574). J.P.P. L.G.-V. O.L.-E. J.B. R.H.A. C.H. L.H. and S.M.R. conceived the project and advanced hypotheses and/or designed experiments. J.P.P. L.G.-V. Y.Z. A.W. J.L. J.X. and Q.M. performed or guided the work. D.M.F. and D.B. provided advice and/or assistance. J.P.P. P.J.H. and S.M.R. wrote the manuscript. The authors declare no competing interests.
Funding Information:
We thank S. Gottesman, J. Imlay, I. Matic, and L. Zechiedrich for E. coli strains, N. Majdalani and S. Kozmin for advice, S. Henikoff for helpful conversation, K.M. Miller and Meng Wang for improving the manuscript, and appreciate the expert assistance of J.M. Sederstrom. This work was supported by NIH ( R35-GM122598 to S.M.R., R01-GM088653 to C.H., R01-GM102679 to D.B., and R01-GM106373 to P.J.H.), the Israeli Science Fund (ISF 1568/13 to L.H.), Baylor College of Medicine (BCM) Integrated Microscopy Core funded by NIH ( DK56338 and CA125123 ) and the Dan L. Duncan Comprehensive Cancer Center , postdoctoral fellowships from the Cancer Prevention and Research Institute of Texas BCM Cancer Training Program , and the American Cancer Society ( RP160283 and 132206-PF-18-035-01-DMC to D.M.F.), the John S. Dunn Gulf Coast Consortium for Chemical Genomics , and the BCM Cytometry and Cell Sorting Core ( NIH P30 AI036211 , P30 CA125123 , and S10 RR024574 ).
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/5/16
Y1 - 2019/5/16
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 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. Bacteria exposed to antibiotic acquire reactive oxygen in a transient “gambler” cell subpopulation that undertakes general stress response-induced mutagenic DNA break repair, evolves resistance to new antibiotics, and is inhibited by an FDA-approved drug that inhibits evolvability.
AB - 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. Bacteria exposed to antibiotic acquire reactive oxygen in a transient “gambler” cell subpopulation that undertakes general stress response-induced mutagenic DNA break repair, evolves resistance to new antibiotics, and is inhibited by an FDA-approved drug that inhibits evolvability.
KW - Escherichia coli
KW - RpoS (σ) stress response
KW - SOS response
KW - antibiotic resistance
KW - error-prone DNA polymerases
KW - evolution
KW - fluoroquinolones
KW - reactive oxygen species
KW - stress-induced mutagenesis
UR - http://www.scopus.com/inward/record.url?scp=85065612145&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065612145&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2019.02.037
DO - 10.1016/j.molcel.2019.02.037
M3 - Article
C2 - 30948267
AN - SCOPUS:85065612145
SN - 1097-2765
VL - 74
SP - 785-800.e7
JO - Molecular Cell
JF - Molecular Cell
IS - 4
ER -