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J Am Chem Soc. 2012 Jan 18;134(2):912-5. doi: 10.1021/ja211042r. Epub 2011 Dec 21.

Benzothiazinones are suicide inhibitors of mycobacterial decaprenylphosphoryl-β-D-ribofuranose 2'-oxidase DprE1.

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More Medicines for Tuberculosis (MM4TB) Consortium, and Institute of Chemical Sciences and Engineering, NCCR Chemical Biology, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.


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.

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