title: Discovery of a quorum sensing modulator pharmacophore by 3D small-molecule microarray screening.
abstract: The screening of large arrays of drug-like small-molecules was traditionally a time consuming and resource intensive task. New methodology developed within our laboratories provides an attractive low cost, 3D microarray-assisted screening platform that could be used to rapidly assay thousands of compounds. As a proof-of-principle the platform was exploited to screen a number of quorum sensing analogs. Quorum sensing is used by bacterium to initiate and spread infection; in this context its modulation may have significant clinical value. 3D microarray slides were probed with fluorescently labeled ligand-binding domains of the LuxR homolog CarR from Erwinia carotovora subsp. carotovora. The 3D microarray platform was used to discover the biologically active chloro-pyridine pharmacophore, which was validated using a fluorometric ligand binding assay and ITC. Analogs containing the chloro-pyridine pharmacophore were found to be potent inhibitors of N-acyl-homoserine-lactone (AHL) mediated quorum sensing phenotypes in Serratia (IC(50) = ∼5 μM) and Pseudomonas aeruginosa (IC(50) = 10-20 μM).
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UKCB2 1EW.
authors.forename: David M
authors.initials: DM
authors.lastname: Marsden
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Nicholson
authors.forename: Mette E
authors.initials: ME
authors.lastname: Skindersoe
authors.forename: Warren R J D
authors.initials: WR
authors.lastname: Galloway
authors.forename: Hannah F
authors.initials: HF
authors.lastname: Sore
authors.forename: Michael
authors.initials: M
authors.lastname: Givskov
authors.forename: George P C
authors.initials: GP
authors.lastname: Salmond
authors.forename: Mark
authors.initials: M
authors.lastname: Ladlow
authors.forename: Martin
authors.initials: M
authors.lastname: Welch
authors.forename: David R
authors.initials: DR
authors.lastname: Spring
mesh_terms: D015394:Molecular Structure; D016973:Pectobacterium carotovorum / Q000737:chemistry; D053038:Quorum Sensing; D054852:Small Molecule Libraries / Q000737:chemistry*
chemical_list: D054852:Small Molecule Libraries