Format

Send to

Choose Destination
PLoS Pathog. 2014 Aug 21;10(8):e1004321. doi: 10.1371/journal.ppat.1004321. eCollection 2014 Aug.

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

Author information

1
Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States of America; Shriners Hospitals for Children Boston, Boston, Massachusetts, United States of America.
2
INRS-Institut Armand Frappier, Laval, Québec, Canada.
3
NMR Surgical Laboratory, Department of Surgery, Massachusetts General and Shriners Hospitals, Harvard Medical School, Boston, Massachusetts, United States of America; Athinoula A. Martinos Center of Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.

Abstract

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.

PMID:
25144274
PMCID:
PMC4140854
DOI:
10.1371/journal.ppat.1004321
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center