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

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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 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.

Original languageEnglish (US)
Pages (from-to)785-800.e7
JournalMolecular cell
Volume74
Issue number4
DOIs
StatePublished - May 16 2019

Fingerprint

Oxygen
Anti-Bacterial Agents
Mutagenesis
DNA Breaks
United States Food and Drug Administration
Ciprofloxacin
DNA Repair
Reactive Oxygen Species
Chromosomes
Mutation
Fluoroquinolones
DNA-Directed DNA Polymerase
Microbial Drug Resistance
Pharmaceutical Preparations
Cell Division
DNA Damage
Electrons
Escherichia coli
Bacteria

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Keywords

  • Escherichia coli
  • RpoS (σ) stress response
  • SOS response
  • antibiotic resistance
  • error-prone DNA polymerases
  • evolution
  • fluoroquinolones
  • reactive oxygen species
  • stress-induced mutagenesis

Cite this

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title = "Gamblers: An Antibiotic-Induced Evolvable Cell Subpopulation Differentiated by Reactive-Oxygen-Induced General Stress Response",
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 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.",
keywords = "Escherichia coli, RpoS (σ) stress response, SOS response, antibiotic resistance, error-prone DNA polymerases, evolution, fluoroquinolones, reactive oxygen species, stress-induced mutagenesis",
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T2 - An Antibiotic-Induced Evolvable Cell Subpopulation Differentiated by Reactive-Oxygen-Induced General Stress Response

AU - Austin, Robert H.

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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.

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