Benzothiazinones: Prodrugs That Covalently Modify the Decaprenylphosphoryl-β-<scp>d</scp>-ribose 2′-epimerase DprE1 of <i>Mycobacterium tuberculosis</i>

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.