ppGpp and RNA-polymerase backtracking guide antibiotic-induced mutable gambler cells
570
antibiotic resistance
Medical Sciences
Biophysics
610
Guanosine Tetraphosphate
Biochemistry
Biomedical Informatics
03 medical and health sciences
ppGpp
Ciprofloxacin
evolution
Medical Specialties
Medicine and Health Sciences
Escherichia coli
stress-induced mutagenesis
fluoroquinolones
Biology
reactive oxygen species
0303 health sciences
Escherichia coli Proteins
Bacterial
Life Sciences
stringent response
DNA-Directed RNA Polymerases
DNA
Gene Expression Regulation, Bacterial
mutations
mutagenic break repair
Anti-Bacterial Agents
Gene Expression Regulation
general stress response
and Structural Biology
RNA
DOI:
10.1016/j.molcel.2023.03.003
Publication Date:
2023-03-24T14:43:23Z
AUTHORS (7)
ABSTRACT
SUMMARYAntibiotics can induce mutations that cause antibiotic resistance, triggered by stress responses. The identities of the stress-response activators reveal environmental cues that elicit mutagenesis, and are weak links in mutagenesis networks, inhibition of which could slow evolution of resistance during antibiotic therapies. Despite pivotal importance, few identities and fewer functions of stress responses in mutagenesis are clear. Here, we identify the stringent starvation response in fluoroquinolone-antibiotic ciprofloxacin (stress)-induced mutagenesis. We show its role in transient differentiation of a mutable “gambler” cell subpopulation. Stringent activity is induced by reactive oxygen and upregulates two small (s)RNAs that induce the general stress response, which allows mutagenic DNA-break repair. Surprisingly, RNA polymerase and response-activator nucleotide (p)ppGpp promote ciprofloxacin-induced DNA-damage signaling. We propose a model for their regulation of DNA-damage processing in transcribed regions. The data demonstrate a critical node in ciprofloxacin-induced mutagenesis, imply RNA-polymerase regulation of DNA-break repair, and identify promising targets for resistance-resisting drugs.
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CITATIONS (20)
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