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Anti-virulent Disruption of Pathogenic Biofilms using Engineered Quorum-quenching Lactonases
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Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity

Melissa Starkey1, Francois Lepine2, Damien Maura1

  • 1Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States of America; Shriners Hospitals for Children Boston, Boston, Massachusetts, United States of America.

Plos Pathogens
|August 22, 2014
PubMed

Insights

New benzamide-benzimidazole compounds target the MvfR quorum sensing pathway in Pseudomonas aeruginosa. These molecules inhibit virulence and reduce antibiotic tolerance without affecting bacterial growth, offering novel therapeutic potential.

Area of Science:

  • Microbiology
  • Bacterial Pathogenesis
  • Drug Discovery

Background:

  • Antibiotic resistance and tolerance pose significant challenges in treating bacterial infections.
  • Pseudomonas aeruginosa is a major opportunistic pathogen causing difficult-to-treat infections.
  • Targeting virulence pathways offers a strategy to combat antibiotic resistance.

Purpose of the Study:

  • To identify novel molecules that inhibit Pseudomonas aeruginosa virulence without promoting resistance.
  • To specifically target the MvfR-regulated quorum sensing (QS) pathway.
  • To develop therapeutics for acute and persistent P. aeruginosa infections.

Main Methods:

  • Whole-cell high-throughput screening (HTS) to identify inhibitors.
  • Structure-activity relationship (SAR) analysis to optimize compounds.
  • In vitro and in vivo testing against P. aeruginosa infections.

Main Results:

  • Identified benzamide-benzimidazole compounds targeting the MvfR transcriptional regulator.
  • Compounds inhibit MvfR-regulated virulence factors and QS signaling molecules.
  • Demonstrated efficacy in murine models of acute and persistent P. aeruginosa infection.
  • Showed no impact on bacterial growth or viability and reduced persister cell formation.

Conclusions:

  • Novel MvfR inhibitors offer a promising strategy against multidrug-resistant P. aeruginosa.
  • These compounds represent a new class of therapeutics for refractory bacterial infections.
  • The findings pave the way for next-generation treatments mitigating antibiotic tolerance and resistance.

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