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

• Published in: PLoS pathogens Vol. 10; no. 8; p. e1004321
• Main Authors: Starkey, Melissa, Lepine, Francois, Maura, Damien, Bandyopadhaya, Arunava, Lesic, Biljana, He, Jianxin, Kitao, Tomoe, Righi, Valeria, Milot, Sylvain, Tzika, Aria, Rahme, Laurence
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.08.2014; Public Library of Science (PLoS)
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Antibiotics; Bacterial infections; Bacteriology; Biology and Life Sciences; Chromatin Immunoprecipitation; Communications systems; Data processing; Disease Models, Animal; Drug Discovery; Drug resistance; Drug Resistance, Bacterial - drug effects; Drug Resistance, Multiple - drug effects; Experiments; Health aspects; Infections; Life Sciences; Medicine and Health Sciences; Mice; Microbiology and Parasitology; Molecular weight; Pseudomonas aeruginosa - drug effects; Pseudomonas Infections - microbiology; Quorum sensing; Quorum Sensing - physiology; Virulence (Microbiology); Virulence - drug effects; Massachusetts
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1004321

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.