Discovery of a quorum sensing modulator pharmacophore by 3D small-molecule microarray screening

TY - JOUR

T1 - Discovery of a quorum sensing modulator pharmacophore by 3D small-molecule microarray screening

AU - Marsden, David M

AU - Nicholson, Rebecca L

AU - Skindersoe, Mette E

AU - Galloway, Warren R J D

AU - Sore, Hannah F

AU - Givskov, Michael

AU - Salmond, George P C

AU - Ladlow, Mark

AU - Welch, Martin

AU - Spring, David R

PY - 2010/12/7

Y1 - 2010/12/7

N2 - 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).

AB - 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).

KW - Molecular Structure

KW - Pectobacterium carotovorum

KW - Quorum Sensing

KW - Small Molecule Libraries

U2 - 10.1039/c0ob00300j

DO - 10.1039/c0ob00300j

M3 - Journal article

C2 - 20886127

SN - 1477-0520

VL - 8

SP - 5313

EP - 5323

JO - Organic & Biomolecular Chemistry

JF - Organic & Biomolecular Chemistry

IS - 23

ER -