title: IspC as target for antiinfective drug discovery: synthesis, enantiomeric separation, and structural biology of fosmidomycin thia isosters.
abstract: The emergence and spread of multidrug-resistant pathogens are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the synthesis and properties of "reverse" thia analogs of fosmidomycin, which inhibit the first committed enzyme of a metabolic pathway that is essential for the causative agents of tuberculosis and malaria but is absent in the human host. Notably, IspC displays a high level of enantioselectivity for an α-substituted fosmidomycin derivative.
authors.affiliation: Center for Integrated Protein Science Munich, Lehrstuhl für Biochemie, Technische Universität München , Lichtenbergstrasse 4, 85747 Garching, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kunfermann
authors.forename: Claudia
authors.initials: C
authors.lastname: Lienau
authors.forename: Boris
authors.initials: B
authors.lastname: Illarionov
authors.forename: Jana
authors.initials: J
authors.lastname: Held
authors.forename: Tobias
authors.initials: T
authors.lastname: Gräwert
authors.forename: Christoph T
authors.initials: CT
authors.lastname: Behrendt
authors.forename: Philipp
authors.initials: P
authors.lastname: Werner
authors.forename: Saskia
authors.initials: S
authors.lastname: Hähn
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Eisenreich
authors.forename: Ulrich
authors.initials: U
authors.lastname: Riederer
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mordmüller
authors.forename: Adelbert
authors.initials: A
authors.lastname: Bacher
authors.forename: Markus
authors.initials: M
authors.lastname: Fischer
authors.forename: Michael
authors.initials: M
authors.lastname: Groll
authors.forename: Thomas
authors.initials: T
authors.lastname: Kurz
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000379:methods*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013237:Stereoisomerism
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D015800:Protozoan Proteins; D005578:Fosfomycin; C024640:fosmidomycin; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases