Identification of mechanisms modulating chlorhexidine and octenidine susceptibility in Proteus mirabilis

J Appl Microbiol. 2024 Jul 2;135(7):lxae173. doi: 10.1093/jambio/lxae173.

Abstract

Aims: We aimed to identify mechanisms underlying the tolerance of Proteus mirabilis-a common cause of catheter associated urinary tract infection-to the clinically used biocides chlorhexidine (CHD) and octenidine (OCT).

Methods and results: We adapted three clinical isolates to grow at concentrations of 512 µg ml-1 CHD and 128 µg ml-1 OCT. Genetic characterization and complementation studies revealed mutations inactivating the smvR repressor and increasing smvA efflux expression were associated with adaptation to both biocides. Mutations in mipA (encoding the MltA interacting protein) were less prevalent than smvR mutations and only identified in CHD adapted populations. Mutations in the rppA response regulator were exclusive to one adapted isolate and were linked with reduced polymyxin B susceptibility and a predicted gain of function after biocide adaptation. Biocide adaptation had no impact on crystalline biofilm formation.

Conclusions: SmvR inactivation is a key mechanism in both CHD and OCT tolerance. MipA inactivation alone confers moderate protection against CHD, and rppA showed no direct role in either CHD or OCT susceptibility.

Keywords: Proteus mirabilis; biocide tolerance; chlorhexidine; octenidine; urinary tract infection.

MeSH terms

  • Anti-Infective Agents, Local / pharmacology
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Biofilms / drug effects
  • Biofilms / growth & development
  • Catheter-Related Infections / microbiology
  • Chlorhexidine* / pharmacology
  • Disinfectants / pharmacology
  • Drug Resistance, Bacterial / genetics
  • Humans
  • Imines* / pharmacology
  • Microbial Sensitivity Tests
  • Mutation
  • Proteus Infections / microbiology
  • Proteus mirabilis* / drug effects
  • Proteus mirabilis* / genetics
  • Proteus mirabilis* / physiology
  • Pyridines* / pharmacology
  • Urinary Tract Infections / microbiology

Substances

  • octenidine
  • Chlorhexidine
  • Imines
  • Pyridines
  • Bacterial Proteins
  • Anti-Infective Agents, Local
  • Disinfectants