title: Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity.
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.
authors.affiliation: 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.
authors.forename: Melissa
authors.initials: M
authors.lastname: Starkey
authors.affiliation: INRS-Institut Armand Frappier, Laval, Québec, Canada.
authors.forename: Francois
authors.initials: F
authors.lastname: Lepine
authors.affiliation: 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.
authors.forename: Damien
authors.initials: D
authors.lastname: Maura
authors.affiliation: 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.
authors.forename: Arunava
authors.initials: A
authors.lastname: Bandyopadhaya
authors.affiliation: 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.
authors.forename: Biljana
authors.initials: B
authors.lastname: Lesic
authors.affiliation: 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.
authors.forename: Jianxin
authors.initials: J
authors.lastname: He
authors.affiliation: 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.
authors.forename: Tomoe
authors.initials: T
authors.lastname: Kitao
authors.affiliation: 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.
authors.forename: Valeria
authors.initials: V
authors.lastname: Righi
authors.affiliation: INRS-Institut Armand Frappier, Laval, Québec, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Milot
authors.affiliation: 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.
authors.forename: Aria
authors.initials: A
authors.lastname: Tzika
authors.affiliation: 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.
authors.forename: Laurence
authors.initials: L
authors.lastname: Rahme
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D055808:Drug Discovery; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D051379:Mice; D011552:Pseudomonas Infections / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D053038:Quorum Sensing / Q000502:physiology*; D014774:Virulence / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents