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

• DOI: 10.1371/journal.ppat.1004321
• Publication Date: 2014-08-21T18:51:29Z
• Authors: Melissa Starkey; Francois Lepine; Damien Maura; Arunava Bandyopad...; Biljana Lesic; Jianxin He; Tomoe Kitao; Valeria Righi; Sylvain Milot; Aria Tzika; Laurence Rahme
• Keywords: Regulon; Multidrug tolerance; Human pathogen

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