title: Benzothiazinones: prodrugs that covalently modify the decaprenylphosphoryl-β-D-ribose 2'-epimerase DprE1 of Mycobacterium tuberculosis.
abstract: Benzothiazinones (BTZs) form a new class of potent antimycobacterial agents. Although the target of BTZs has been identified as decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1), their detailed mechanism of action remains obscure. Here we demonstrate that BTZs are activated in the bacterium by reduction of an essential nitro group to a nitroso derivative, which then specifically reacts with a cysteine residue in the active site of DprE1.
authors.affiliation: New Medicines for Tuberculosis Consortium, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Trefzer
authors.forename: Monica
authors.initials: M
authors.lastname: Rengifo-Gonzalez
authors.forename: Marlon J
authors.initials: MJ
authors.lastname: Hinner
authors.forename: Patricia
authors.initials: P
authors.lastname: Schneider
authors.forename: Vadim
authors.initials: V
authors.lastname: Makarov
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
authors.forename: Kai
authors.initials: K
authors.lastname: Johnsson
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D011355:Prodrugs; D013843:Thiazines; D019998:Racemases and Epimerases