Details

Autor(en) / Beteiligte

• Starkey, Melissa
• Lepine, Francois
• Maura, Damien
• Bandyopadhaya, Arunava
• Lesic, Biljana
• He, Jianxin
• Kitao, Tomoe
• Righi, Valeria
• Milot, Sylvain
• Tzika, Aria
• Rahme, Laurence
• Whiteley, Marvin

Titel

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

Ist Teil von

• PLoS pathogens, 2014-08, Vol.10 (8), p.e1004321-e1004321

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.