Abstract
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 (SaThiM; EC 2.7.1.50), a potential target for pro-drug compounds and analyzed the native structure of SaThiM and complexes with the natural substrate 5-(hydroxyethyl)-4-methylthiazole (THZ) and two selected substrate analogues.
Highlights
New antibacterial drugs should target metabolic processes that are exclusive to bacteria but absent in humans
The shortfall in the development of new antibiotics and the misguided overuse of the currently available antibiotics has caused an unfortunate spread of multi-resistant bacteria in recent years
To our knowledge this study represents the first approach in targeting the Sa thiazole kinase ThiM of the bacterial vitamin B1 pathway, applying structure based pro-drug discovery
Summary
New antibacterial drugs should target metabolic processes that are exclusive to bacteria (like the vitamin B1 biosynthetic pathway, which is conserved among most bacteria, plants and lower eukaryotes9) but absent in humans. In addition to the native structure, complexes with THZ and two selected lead compounds were analyzed The goal of these investigations was to identify potential pro-drug THZ analogues that do not inhibit ThiM, but will be accepted as substrates, yielding non-functional TPP analogues. It had already been shown that thiamin derivatives having an oxazolium or imidazolium ring are less reactive than thiazolium analogues, since in absence of 3d orbitals the transition state cannot be stabilized[16,17,18] These comparative structural analyses of active site regions in combination with the data obtained from enzymatic assays yielded essential information to further design and optimize potential pro-drug THZ analogues
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