title: Covalent inhibition of bacterial quorum sensing.
abstract: Chemical coordination of gene expression among bacteria as a function of population density is regulated by a mechanism known as 'quorum sensing' (QS). QS in Pseudomonas aeruginosa, an opportunistic pathogen that causes disease in immunocompromised patients, is mediated by binding of the transcriptional activator, LasR, to its ligand, 3-oxo-C(12)-HSL, leading to population-wide secretion of virulence factors and biofilm formation. We have targeted QS in P. aeruginosa with a set of electrophilic probes designed to covalently bind Cys79 in the LasR binding pocket, leading to specific inhibition of QS-regulated gene expression and concomitant reduction of virulence factor secretion and biofilm formation. This first example of covalent modification of a QS receptor provides a new tool to study molecular mechanisms of bacterial group behavior and could lead to new strategies for targeting bacterial virulence.
authors: Department of Chemistry, Ben-Gurion University of the Negev, Be'er Sheva 84105, Israel.
authors: Neri
authors: N
authors: Amara
authors: Roi
authors: R
authors: Mashiach
authors: Dotan
authors: D
authors: Amar
authors: Pnina
authors: P
authors: Krief
authors: Stéphane A H
authors: SA
authors: Spieser
authors: Matthew J
authors: MJ
authors: Bottomley
authors: Amir
authors: A
authors: Aharoni
authors: Michael M
authors: MM
authors: Meijler
mesh_terms: D000478:Alkylation; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D003545:Cysteine / Q000378:metabolism; D017879:Isothiocyanates / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D011549:Pseudomonas / Q000166:cytology*; D053038:Quorum Sensing / Q000187:drug effects*; D013379:Substrate Specificity; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D017879:Isothiocyanates; C080365:LasR protein, Pseudomonas aeruginosa; D015534:Trans-Activators; C037152:isothiocyanic acid; D003545:Cysteine