Identification and characterization of pleiotropic high-persistence mutations in the beta subunit of the bacterial RNA polymerase

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations conferring resistance to bactericidal antibiotics reduce the average susceptibility of mutant populations. It is unknown, however, how those mutations affect the survival of individual bacteria. Since surviving bacteria can be a reservoir for recurring infections, it is important to know how survival rates may be affected by resistance mutations and by the choice of antibiotics. Here, we present evidence that (i) Escherichia coli mutants with 100 to 1,000 times increased frequency of survival in ciprofloxacin, an archetypal fluoroquinolone antibiotic, can be readily obtained in a stepwise selection; (ii) the high survival frequency is conferred by mutations in the switch region of the beta subunit of the RNA polymerase; (iii) the switch-region mutations are (p) ppGpp mimics, partially analogous to rpoB stringent mutations; (iv) the stringent and switch region rpoB mutations frequently occur in clinical isolates of E. coli, Acinetobacter baumannii, Mycobacterium tuberculosis, and Staphylococcus aureus, and at least one of them, RpoB S488L, which is a common rifampicin resistance mutations, dramatically increases the survival of a clinical methicillin-resistant S. aureus (MRSA) strain in ampicillin; and (v) the RpoB-associated high-survival phenotype can be reversed by subinhibitory concentrations of chloramphenicol.

Original languageEnglish (US)
Article numbere00522-21
JournalAntimicrobial agents and chemotherapy
Volume65
Issue number11
DOIs
StatePublished - Nov 2021

Bibliographical note

Publisher Copyright:
© 2021 American Society for Microbiology.

Keywords

  • Antibiotic persistence
  • Antibiotic resistance
  • Ciprofloxacin
  • Escherichia coli
  • Fluoroquinolones
  • MRSA
  • MTB
  • PpGpp
  • RNA polymerase
  • Rifampicin
  • RpoB
  • Stringent response
  • Survival
  • Tolerance

PubMed: MeSH publication types

  • Journal Article

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