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

PLoS Pathogens

Francois Lepine¹  Sylvain Milot¹  Jianxin He¹  Laurence Rahme²  Melissa Starkey²  Biljana Lesic²  Valeria Righi²  Arunava Bandyopadhaya³  Tomoe Kitao⁴  Aria Tzika⁴  Damien Maura⁴ 

[1] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States of America;Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, United States of America;INRS-Institut Armand Frappier, Laval, Québec, Canada;Shriners Hospitals for Children Boston, Boston, Massachusetts, United States of America

关键词: Pseudomonas aeruginosa;    Antibiotics;    Animal models of infection;    Antibiotic resistance;    Macrophages;    Regulons;    Bacterial pathogens;    Magnetic resonance imaging;   

DOI  :  10.1371/journal.ppat.1004321

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY