title: Pseudomonas aeruginosa LasR·DNA Binding Is Directly Inhibited by Quorum Sensing Antagonists.
abstract: Inhibition of quorum sensing in Pseudomonas aeruginosa is of interest as a possible antivirulence strategy for this pathogenic bacterium. The LasR regulator protein is important in coordinating gene expression in response to quorum sensing signaling molecules. One predominant strategy for LasR inhibition is the development of small-molecule antagonists that mimic the native autoinducer, though the mechanism by which they inactivate LasR is not known. This work reveals that multiple antagonists function by binding to and stabilizing LasR in a conformation that renders it unable to bind DNA. Further analysis of purified LasR complexed with known antagonists indicates that DNA binding can be recovered with the addition of native autoinducer, providing insights into the reversibility of ligand binding for this transcription factor. This in vitro assay could be used to assess future promising antagonists and complements existing cell-based reporter assays.
authors.affiliation: Department of Chemistry, Connecticut College , New London, Connecticut 06320, United States.
authors.forename: Emma G
authors.initials: EG
authors.lastname: Suneby
authors.affiliation: Department of Chemistry, Smith College , Northampton, Massachusetts 01063, United States.
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Herndon
authors.affiliation: Department of Chemistry, Connecticut College , New London, Connecticut 06320, United States.
authors.forename: Tanya L
authors.identifier: 0000-0002-0643-0170
authors.initials: TL
authors.lastname: Schneider
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000378:metabolism; D053038:Quorum Sensing / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014774:Virulence / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C080365:LasR protein, Pseudomonas aeruginosa; D054852:Small Molecule Libraries; D015534:Trans-Activators; D004247:DNA
keywords: LasR; Pseudomonas aeruginosa; antivirulence; quorum sensing; transcription factor