Multistep virtual screening for rapid and efficient identification of non-nucleoside bacterial thymidine kinase inhibitors

Chemistry : a European Journal
Johannes ZanderGisbert Schneider

Abstract

Antimicrobial activity of trimethoprim/sulfamethoxazole (SXT) against Staphylococcus aureus (S. aureus) is antagonized by thymidine, which is abundant in infected or inflamed human tissue. To restore the antimicrobial activity of SXT in the presence of thymidine, we screened for small-molecule inhibitors of S. aureus thymidine kinase with non-nucleoside scaffolds. We present the successful application of an adaptive virtual screening protocol for novel antibiotics using a combination of ligand- and structure-based approaches. Two consecutive rounds of virtual screening and in vitro testing were performed that resulted in several non-nucleoside hits. The most potent compound exhibits substantial antimicrobial activity against both methicillin-resistant S. aureus strain ATCC 700699 and nonresistant strain ATCC 29213, when combined with SXT in the presence of thymidine. This study demonstrates how virtual screening can be used to guide hit finding in antibacterial screening campaigns with minimal experimental effort.

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Citations

Mar 18, 2011·Current Opinion in Chemical Biology·Meir Glick, Edgar Jacoby
Jul 23, 2013·ChemMedChem·Antonella Di PizioMariangela Agamennone
Jul 21, 2015·Computational Biology and Chemistry·Utku DenizElif Ozkirimli
Jan 24, 2013·Drug Discovery Today·Yusuf TanrikuluEwgenij Proschak
Jul 1, 2013·Molecular Informatics·Volker HähnkeGisbert Schneider
Jul 26, 2015·Archives of Pharmacal Research·Stephani Joy Y MacalinoSun Choi

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