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Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity.

ABSTRACT: Etiological agents of acute, persistent, or relapsing clinical infections are often refractory to antibiotics due to multidrug resistance and/or antibiotic tolerance. Pseudomonas aeruginosa is an opportunistic Gram-negative bacterial pathogen that causes recalcitrant and severe acute chronic and persistent human infections. Here, we target the MvfR-regulated P. aeruginosa quorum sensing (QS) virulence pathway to isolate robust molecules that specifically inhibit infection without affecting bacterial growth or viability to mitigate selective resistance. Using a whole-cell high-throughput screen (HTS) and structure-activity relationship (SAR) analysis, we identify compounds that block the synthesis of both pro-persistence and pro-acute MvfR-dependent signaling molecules. These compounds, which share a benzamide-benzimidazole backbone and are unrelated to previous MvfR-regulon inhibitors, bind the global virulence QS transcriptional regulator, MvfR (PqsR); inhibit the MvfR regulon in multi-drug resistant isolates; are active against P. aeruginosa acute and persistent murine infections; and do not perturb bacterial growth. In addition, they are the first compounds identified to reduce the formation of antibiotic-tolerant persister cells. As such, these molecules provide for the development of next-generation clinical therapeutics to more effectively treat refractory and deleterious bacterial-human infections.

SUBMITTER: Starkey M

PROVIDER: S-EPMC4140854 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity.

Starkey Melissa M Lepine Francois F Maura Damien D Bandyopadhaya Arunava A Lesic Biljana B He Jianxin J Kitao Tomoe T Righi Valeria V Milot Sylvain S Tzika Aria A Rahme Laurence L

PLoS pathogens 20140821 8

Etiological agents of acute, persistent, or relapsing clinical infections are often refractory to antibiotics due to multidrug resistance and/or antibiotic tolerance. Pseudomonas aeruginosa is an opportunistic Gram-negative bacterial pathogen that causes recalcitrant and severe acute chronic and persistent human infections. Here, we target the MvfR-regulated P. aeruginosa quorum sensing (QS) virulence pathway to isolate robust molecules that specifically inhibit infection without affecting bacte ...[more]

PMID: 25144274

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Dataset Information

Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity.

Publications

Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity.

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