title: Synthesis and biological evaluation of triazole-containing N-acyl homoserine lactones as quorum sensing modulators.
abstract: Many bacterial species are capable of assessing their local population densities through a cell-cell signaling mechanism termed quorum sensing (QS). This intercellular communication process is mediated by small molecule or peptide ligands and their cognate protein receptors. Numerous pathogens use QS to initiate virulence once they achieve a threshold cell number on a host. Consequently, approaches to intercept QS have attracted considerable attention as potential anti-infective therapies. Our interest in the development of small molecule tools to modulate QS pathways motivated us to evaluate triazole-containing analogs of natural N-acyl L-homoserine lactone (AHL) signals as non-native QS agonists and antagonists in Gram-negative bacteria. We synthesized 72 triazole derivatives of five broad structure types in high yields and purities using efficient Cu(I)-catalyzed azide-alkyne couplings. These compounds were evaluated for their ability to activate or inhibit two QS receptors from two prevalent pathogens - LasR from Pseudomonas aeruginosa and AbaR from Acinetobacter baumannii- using bacterial reporter strains. Several triazole derivatives were identified that were capable of strongly modulating the activity of LasR and AbaR. These compounds represent a new and synthetically accessible class of AHL analogs, and could find utility as chemical tools to study QS and its role in bacterial virulence.
authors.affiliation: Department of Chemistry, University of Wisconsin-Madison, 1101 University Ave., Madison, WI 53706, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Stacy
authors.forename: Sebastian T
authors.initials: ST
authors.lastname: Le Quement
authors.forename: Casper L
authors.initials: CL
authors.lastname: Hansen
authors.forename: Janie W
authors.initials: JW
authors.lastname: Clausen
authors.forename: Tim
authors.initials: T
authors.lastname: Tolker-Nielsen
authors.forename: Jacob W
authors.initials: JW
authors.lastname: Brummond
authors.forename: Michael
authors.initials: M
authors.lastname: Givskov
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Nielsen
authors.forename: Helen E
authors.initials: HE
authors.lastname: Blackwell
mesh_terms: D054742:Acyl-Butyrolactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000819:agonists*; D020128:Inhibitory Concentration 50; D053038:Quorum Sensing; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors; D015534:Trans-Activators / Q000819:agonists*; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D054742:Acyl-Butyrolactones; D001426:Bacterial Proteins; C080365:LasR protein, Pseudomonas aeruginosa; D054852:Small Molecule Libraries; D015534:Trans-Activators; D014230:Triazoles