ppGpp and RNA-Polymerase Backtracking Guide Antibiotic-Induced Mutable Gambler Cells

Authors

Yin Zhai
P J Minnick
John P Pribis
Libertad Garcia-Villada
P J Hastings
Christophe Herman
Susan M Rosenberg

Publication Date

4-20-2023

Journal

Moecular Cell

DOI

10.1016/j.molcel.2023.03.003

PMID

36965481

PMCID

PMC10317147

PubMedCentral® Posted Date

7-3-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Escherichia coli Proteins, Guanosine Tetraphosphate, Anti-Bacterial Agents, Escherichia coli, DNA-Directed RNA Polymerases, Ciprofloxacin, DNA, RNA, Gene Expression Regulation, Bacterial, antibiotic resistance, evolution, fluoroquinolones, general stress response, mutations, mutagenic break repair, ppGpp, reactive oxygen species, stress-induced mutagenesis, stringent response

Abstract

Antibiotic resistance is a global health threat and often results from new mutations. Antibiotics can induce mutations via mechanisms activated by stress responses, which both reveal environmental cues of mutagenesis and are weak links in mutagenesis networks. Network inhibition could slow the evolution of resistance during antibiotic therapies. Despite its pivotal importance, few identities and fewer functions of stress responses in mutagenesis are clear. Here, we identify the Escherichia coli stringent starvation response in fluoroquinolone-antibiotic ciprofloxacin-induced mutagenesis. Binding of response-activator ppGpp to RNA polymerase (RNAP) at two sites leads to an antibiotic-induced mutable gambler-cell subpopulation. Each activates a stress response required for mutagenic DNA-break repair: surprisingly, ppGpp-site-1-RNAP triggers the DNA-damage response, and ppGpp-site-2-RNAP induces σ

Comments

Associated Data