Discovery of a quorum sensing modulator pharmacophore by 3D small-molecule microarray screening.
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).
Marsden
David M
DM
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UKCB2 1EW.
Nicholson
Rebecca L
RL
Skindersoe
Mette E
ME
Galloway
Warren R J D
WR
Sore
Hannah F
HF
Givskov
Michael
M
Salmond
George P C
GP
Ladlow
Mark
M
Welch
Martin
M
Spring
David R
DR
D015394:Molecular Structure; D016973:Pectobacterium carotovorum / Q000737:chemistry; D053038:Quorum Sensing; D054852:Small Molecule Libraries / Q000737:chemistry*
D054852:Small Molecule Libraries