Drebes, J.J.DrebesKünz, M.M.KünzWindshügel, B.B.WindshügelKikhney, A.G.A.G.KikhneyMüller, I.B.I.B.MüllerEberle, R.J.R.J.EberleOberthür, D.D.OberthürCang, H.H.CangSvergun, D.I.D.I.SvergunPerbandt, M.M.PerbandtBetzel, C.C.BetzelWrenger, C.C.Wrenger2022-03-052022-03-052016https://publica.fraunhofer.de/handle/publica/24480710.1038/srep22871Infections 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 2.7.1.50), 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.enjournal article