title: Structure of ThiM from Vitamin B1 biosynthetic pathway of Staphylococcus aureus - Insights into a novel pro-drug approach addressing MRSA infections.
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.
authors.affiliation: University Hamburg, c/o DESY, Laboratory for Structural Biology of Infection and Inflammation, Hamburg, Germany.|Department of Biochemistry, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Drebes
authors.affiliation: University Hamburg, c/o DESY, Laboratory for Structural Biology of Infection and Inflammation, Hamburg, Germany.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Künz
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Hamburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Windshügel
authors.affiliation: EMBL Hamburg, c/o DESY, Hamburg, Germany.
authors.forename: Alexey G
authors.initials: AG
authors.lastname: Kikhney
authors.affiliation: Department of Biochemistry, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Müller
authors.affiliation: University Hamburg, c/o DESY, Laboratory for Structural Biology of Infection and Inflammation, Hamburg, Germany.
authors.forename: Raphael J
authors.initials: RJ
authors.lastname: Eberle
authors.affiliation: University Hamburg, c/o DESY, Laboratory for Structural Biology of Infection and Inflammation, Hamburg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Oberthür
authors.affiliation: School of Life Sciences North Western Polytechnical University, Xi'an,Shaanxi, China.
authors.forename: Huaixing
authors.initials: H
authors.lastname: Cang
authors.affiliation: EMBL Hamburg, c/o DESY, Hamburg, Germany.
authors.forename: Dmitri I
authors.initials: DI
authors.lastname: Svergun
authors.affiliation: University Hamburg, c/o DESY, Laboratory for Structural Biology of Infection and Inflammation, Hamburg, Germany.|The Hamburg Centre for Ultrafast Imaging, Luruper Chaussee 149, D-22761 Hamburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Perbandt
authors.affiliation: University Hamburg, c/o DESY, Laboratory for Structural Biology of Infection and Inflammation, Hamburg, Germany.|The Hamburg Centre for Ultrafast Imaging, Luruper Chaussee 149, D-22761 Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Betzel
authors.affiliation: Unit for Drug Discovery, Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Carsten
authors.initials: C
authors.lastname: Wrenger
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry*; D053898:Biosynthetic Pathways; D020134:Catalytic Domain; D062126:Databases, Chemical; D016106:Methicillin Resistance; D008958:Models, Molecular; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D013211:Staphylococcus aureus / Q000201:enzymology*; D013831:Thiamine / Q000096:biosynthesis*; D013844:Thiazoles / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D011355:Prodrugs; D013844:Thiazoles; C012572:2-(4-methyl-1,3-thiazol-5-yl)ethanol; D017853:Phosphotransferases (Alcohol Group Acceptor); D013831:Thiamine