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Antibacterial agent discovery using thymidylate synthase biolibrary screening.

M Paola Costi·Arianna Gelain·Daniela Barlocco·Stefano Ghelli·Fabrizia Soragni·Fabiano Reniero·Tiziana Rossi·Antonio Ruberto·Claude Guillou·Antonio Cavazzuti·Chiara Casolari·Stefania Ferrari
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Abstract

Thymidylate synthase (TS, ThyA) catalyzes the reductive methylation of 2'-deoxyuridine 5'-monophosphate to 2'-deoxythymidine 5'-monophosphate, an essential precursor for DNA synthesis. A specific inhibition of this enzyme induces bacterial cell death. As a second round lead optimization design, new 1,2-naphthalein derivatives have been synthesized and tested against a TS-based biolibrary, including human thymidylate synthase (hTS). Docking studies have been performed to rationalize the experimentally observed affinity profiles of 1,2-naphthalein compounds toward Lactobacillus casei TS and hTS. The best TS inhibitors have been tested against a number of clinical isolates of Gram-positive-resistant bacterial strains. Compound 3,3-bis(3,5-dibromo-4-hydroxyphenyl)-1H,3H-naphtho[1,2-c]furan-1-one (5) showed significant antibacterial activity, no in vitro toxicity, and dose-response effects against Staphylococcus epidermidis (MIC=0.5-2.5 microg/mL) clinical isolate strains, which are resistant to at least 17 of the best known antibacterial agents, including vancomycin. So far this compound can be regarded as a leading antibacterial agent.

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AnimalsAnti-Bacterial AgentsBacterial ProteinsBenzofuransChlorocebus aethiopsCitrobacterCryptococcus neoformansDatabases, FactualDrug Resistance, Multiple, BacterialEnterococcusEscherichia coliHumansLacticaseibacillus caseiListeria monocytogenesMicrobial Sensitivity TestsModels, MolecularNaphthalenesStaphylococcusStreptococcusStructure-Activity RelationshipTetrahydrofolate DehydrogenaseThymidylate SynthaseVero CellsJournal ArticleResearch Support, Non-U.S. Gov't

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M Paola Costi, Arianna Gelain, Daniela Barlocco, Stefano Ghelli, Fabrizia Soragni, Fabiano Reniero, Tiziana Rossi, Antonio Ruberto, Claude Guillou, Antonio Cavazzuti, Chiara Casolari, Stefania Ferrari. 2006-10-05. Antibacterial agent discovery using thymidylate synthase biolibrary screening.. https://doi.org/10.1021/jm051187d

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