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Structure of ThiM from Vitamin B1 biosynthetic pathway of Staphylococcus aureus - Insights into a novel pro-drug approach addressing MRSA infections

: Drebes, J.; Künz, M.; Windshügel, B.; Kikhney, A.G.; Müller, I.B.; Eberle, R.J.; Oberthür, D.; Cang, H.; Svergun, D.I.; Perbandt, M.; Betzel, C.; Wrenger, C.

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Scientific Reports 6 (2016), Art. 22871, 10 S.
ISSN: 2045-2322
Bundesministerium für Bildung und Forschung BMBF
Zeitschriftenaufsatz, Elektronische Publikation
Fraunhofer IME ()

Infections caused by the methicillin-resistant Staphylococcus aureus (MRSA) are today known to be a substantial threat for global health. Emerging multi-drug resistant bacteria have created a substantial need to identify and discover new drug targets and to develop novel strategies to treat bacterial infections. A promising and so far untapped antibiotic target is the biosynthesis of vitamin B1 (thiamin). Thiamin in its activated form, thiamin pyrophosphate, is an essential co-factor for all organisms. Therefore, thiamin analogous compounds, when introduced into the vitamin B1 biosynthetic pathway and further converted into non-functional co-factors by the bacterium can function as pro-drugs which thus block various co-factor dependent pathways. We characterized one of the key enzymes within the S. aureus vitamin B1 biosynthetic pathway, 5-(hydroxyethyl)-4-methylthiazole kinase (S alpha ThiM; EC, a potential target for pro-drug compounds and analyzed the native structure of S alpha ThiM and complexes with the natural substrate 5-(hydroxyethyl)-4-methylthiazole (THZ) and two selected substrate analogues.