Discovery of a quorum sensing modulator pharmacophore by 3D small-molecule microarray screening
| Autor: | Hannah F. Sore, David M. Marsden, Mette E. Skindersoe, Martin Welch, Mark Ladlow, Rebecca L. Nicholson, George P. C. Salmond, David R. Spring, Warren R. J. D. Galloway, Michael Givskov |
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| Rok vydání: | 2010 |
| Předmět: |
Molecular Structure
Microarray Pseudomonas aeruginosa Chemistry Ligand binding assay Organic Chemistry Quorum Sensing food and beverages Context (language use) Biological activity Computational biology medicine.disease_cause Biochemistry Small molecule Microbiology Small Molecule Libraries Quorum sensing Pectobacterium carotovorum medicine Physical and Theoretical Chemistry Pharmacophore |
| Zdroj: | Organic & Biomolecular Chemistry. 8:5313 |
| ISSN: | 1477-0539 1477-0520 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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