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Using a Bacterial Pathogen to Probe for Cellular and Organismic-level Host Responses
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Bacterial efflux pump modulators prevent bacterial growth in macrophages and under broth conditions that mimic the

Samual C Allgood1, Chih-Chia Su2,3, Amy L Crooks1

  • 1Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, Colorado, USA.

Mbio
|November 3, 2023
PubMed
Abstract

Insights

New efflux pump modulators (EPMs) combat bacterial infections by enhancing antibiotic effectiveness and enabling toxic metabolite buildup. These compounds offer a dual strategy against antibiotic resistance and pathogen virulence.

Area of Science:

  • Microbiology
  • Medicinal Chemistry
  • Structural Biology

Background:

  • Bacterial efflux pumps are key mechanisms for antibiotic resistance and pathogen virulence.
  • Previously identified efflux pump modulators (EPMs) showed potential in inhibiting pathogen replication.
  • Enhancing EPM activity is crucial for developing novel antimicrobial strategies.

Purpose of the Study:

  • To develop highly active efflux pump modulators (EPMs) with nanomolar potency.
  • To elucidate the binding mechanism of EPMs to bacterial efflux pump subunits.
  • To investigate the impact of EPMs on antibiotic efficacy and bacterial metabolism.

Main Methods:

  • Medicinal chemistry optimization of lead EPM compounds.
  • Cryo-electron microscopy for structural analysis of EPM-efflux pump interactions.
  • Broth microdilution assays to assess antibiotic potentiation and bacterial growth inhibition.

Main Results:

  • Optimized EPMs achieved nanomolar activity against bacterial pathogens.
  • Cryo-EM revealed that EPMs bind to a specific efflux pump subunit.
  • EPMs increased antibiotic potency but not efficacy, and led to toxic metabolite accumulation.

Conclusions:

  • Enhanced EPMs represent a promising therapeutic strategy against bacterial infections.
  • EPMs offer a dual mechanism of action: potentiating antibiotics and disrupting bacterial homeostasis.
  • Efflux pumps are essential for virulence, potentially due to their role in exporting toxic metabolites.
Keywords:
AcrAB-TolCGram-negative bacteriaSAFIREcryo-electron microscopyefflux pumpmacrophage

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