title: Benzothiazinones are suicide inhibitors of mycobacterial decaprenylphosphoryl-β-D-ribofuranose 2'-oxidase DprE1.
abstract: Benzothiazinones (BTZs) are antituberculosis drug candidates with nanomolar bactericidal activity against tubercle bacilli. Here we demonstrate that BTZs are suicide substrates of the FAD-dependent decaprenylphosphoryl-β-D-ribofuranose 2'-oxidase DprE1, an enzyme involved in cell-wall biogenesis. BTZs are reduced by DprE1 to an electrophile, which then reacts in a near-quantitative manner with an active-site cysteine of DprE1, thus providing a rationale for the extraordinary potency of BTZs. Mutant DprE1 enzymes from BTZ-resistant strains reduce BTZs to inert metabolites while avoiding covalent inactivation. Our results explain the basis for drug sensitivity and resistance to an exceptionally potent class of antituberculosis agents.
authors.affiliation: More Medicines for Tuberculosis (MM4TB) Consortium, and Institute of Chemical Sciences and Engineering, NCCR Chemical Biology, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Trefzer
authors.forename: Henrieta
authors.initials: H
authors.lastname: Škovierová
authors.forename: Silvia
authors.initials: S
authors.lastname: Buroni
authors.forename: Adela
authors.initials: A
authors.lastname: Bobovská
authors.forename: Simone
authors.initials: S
authors.lastname: Nenci
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Molteni
authors.forename: Florence
authors.initials: F
authors.lastname: Pojer
authors.forename: Maria R
authors.initials: MR
authors.lastname: Pasca
authors.forename: Vadim
authors.initials: V
authors.lastname: Makarov
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
authors.forename: Giovanna
authors.initials: G
authors.lastname: Riccardi
authors.forename: Katarína
authors.initials: K
authors.lastname: Mikušová
authors.forename: Kai
authors.initials: K
authors.lastname: Johnsson
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D009161:Mycobacterium / Q000201:enzymology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D010088:Oxidoreductases