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Pimozide Inhibits the AcrAB-TolC Efflux Pump in Escherichia coli

Jürgen A Bohnert1, Sabine Schuster, Winfried V Kern

  • 1Center for Infectious Diseases and Travel Medicine, University Hospital, and Department of Medicine, Albert-Ludwigs-University, Freiburg, Germany.

The Open Microbiology Journal
|April 6, 2013
PubMed

Insights

Pimozide fully inhibited the Escherichia coli AcrAB-TolC efflux pump in vitro. However, it only slightly reduced the minimum inhibitory concentrations (MICs) of most tested antimicrobial agents, suggesting substrate-specific efficacy for efflux pump inhibitors.

Area of Science:

  • Microbiology
  • Pharmacology
  • Biochemistry

Background:

  • Multidrug resistance in bacterial pathogens is a significant clinical challenge.
  • Efflux pump inhibitors (EPIs) are investigated for their potential to reverse this resistance.
  • The Escherichia coli AcrAB-TolC efflux pump is a key contributor to multidrug resistance.

Purpose of the Study:

  • To evaluate the neuroleptic drug pimozide as an inhibitor of the E. coli AcrAB-TolC efflux pump.
  • To determine if pimozide can restore susceptibility to various antimicrobial agents.

Main Methods:

  • Real-time Nile red efflux assay to assess pump inhibition.
  • Minimum Inhibitory Concentration (MIC) assays for various antimicrobial compounds.
  • Ethidium bromide accumulation and MIC assays to evaluate substrate-specific effects.

Main Results:

  • Pimozide demonstrated full inhibition of the AcrAB-TolC efflux pump at 100 µM.
  • Pimozide showed minimal reduction in MICs for most tested antimicrobials, except for a twofold reduction in oxacillin MICs.
  • Pimozide significantly enhanced ethidium bromide accumulation and reduced its MIC by fourfold.

Conclusions:

  • Pimozide effectively inhibits the E. coli AcrAB-TolC efflux pump.
  • The ability of EPIs to restore antimicrobial susceptibility is highly substrate-specific.
  • Different substrate binding sites may explain the variable efficacy of EPIs against different antimicrobial agents.
Keywords:
AcrBefflux pump inhibitormultidrug resistancepimozide.

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