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Issue 23, 2010
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Discovery of a quorum sensing modulator pharmacophore by 3D small-molecule microarray screening

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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 (IC50 = ∼5 μM) and Pseudomonas aeruginosa (IC50 = 10–20 μM).

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

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Publication details

The article was received on 22 Jun 2010, accepted on 23 Aug 2010 and first published on 30 Sep 2010


Article type: Paper
DOI: 10.1039/C0OB00300J
Org. Biomol. Chem., 2010,8, 5313-5323

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

    D. M. Marsden, R. L. Nicholson, M. E. Skindersoe, W. R. J. D. Galloway, H. F. Sore, M. Givskov, G. P. C. Salmond, M. Ladlow, M. Welch and D. R. Spring, Org. Biomol. Chem., 2010, 8, 5313
    DOI: 10.1039/C0OB00300J

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