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: 0301 basic medicine; 570; Chromatin Immunoprecipitation; Drug Research and Development; QH301-705.5; -; Microbiology; Mice; 03 medical and health sciences; Microbial Control; 616; Drug Discovery; Drug Resistance, Bacterial; Medicine and Health Sciences; Animals; Pseudomonas Infections; Biology (General); Microbial Pathogens; Pharmacology; Virulence; Biology and Life Sciences; Quorum Sensing; RC581-607; Drug Resistance, Multiple; Bacterial Pathogens; Anti-Bacterial Agents; 3. Good health; [SDV] Life Sciences [q-bio]; Disease Models, Animal; Small Molecules; Medical Microbiology; 13. Climate action; Animals; Anti-Bacterial Agents; Chromatin Immunoprecipitation; Disease Models, Animal; Drug Resistance, Bacterial; Drug Resistance, Multiple; Mice; Pseudomonas Infections; Pseudomonas aeruginosa; Quorum Sensing; Virulence; Drug Discovery; Parasitology; Microbiology; Immunology; Molecular Biology; Genetics; Virology; Pseudomonas aeruginosa; [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology; Immunologic diseases. Allergy; Biotechnology; Research Article

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.