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

Melissa Starkey (1, 2, 3) , Francois Lepine (4) , Damien Maura (1, 2, 3) , Arunava Bandyopadhaya (1, 2, 3) , Biljana Lesic (1, 2, 3) , Jianxin He (1, 2, 3) , Tomoe Kitao (1, 2, 3) , Valeria Righi (5, 6) , Sylvain Milot (4) , Aria Tzika (5, 6) , Laurence Rahme (1, 2, 3)

1 Department of Surgery
2 Department of Microbiology and Immunobiology
3 Shriners Hospitals for Children [Boston]
4 INRS-IAF - Institut Armand Frappier
5 NMR Surgical Laboratory, Department of Surgery
6 Athinoula A. Martinos Center of Biomedical Imaging, Department of Radiology

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.

Domaines: Sciences du Vivant [q-bio]; Bactériologie

Melissa Starkey, Francois Lepine, Damien Maura, Arunava Bandyopadhaya, Biljana Lesic, et al.. Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity.. PLoS Pathogens, 2014, 10 (8), pp.e1004321. ⟨10.1371/journal.ppat.1004321⟩. ⟨pasteur-01136267⟩