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Identification of Anti-virulence Compounds That Disrupt Quorum-Sensing Regulated Acute and Persistent Pathogenicity

Starkey, Mélissa; Lépine, François; Maura, Damien; Bandyopadhaya, Arunava; Lesic, Biliana; He, Jianxin; Kitao, Tomoe; Righi, Valéria; Milot, Sylvain; Tzika, Aria; Rahme, Laurence G. (2014). Identification of Anti-virulence Compounds That Disrupt Quorum-Sensing Regulated Acute and Persistent Pathogenicity PLoS Pathogens , vol. 10 , nº 8. e1004321. DOI: 10.1371/journal.ppat.1004321.

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Résumé

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.

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Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 09 mars 2016 21:55
Dernière modification: 22 déc. 2016 20:10
URI: http://espace.inrs.ca/id/eprint/3117

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