Basis for benzothiazinone sensitivity of tubercle bacilli.

© 2012 EPFL

Benzothiazinones Are Suicide Inhibitors of Mycobacterial Decaprenylphosphoryl-β-d-ribofuranose 2′-Oxidase DprE1.

Benzothiazinones (BTZs) are antituberculosis drug candidates with nanomolar bactericidal activity against tubercle bacilli. Here, Profs. S. Cole ( Chair of Microbial Pathogenesis - UPCOL) and K. Johnsson (LIP - Laboratory of Protein Engineering ) and their collaborators 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. Their results explain the basis for drug sensitivity and resistance to an exceptionally potent class of antituberculosis agents.

Claudia Trefzer et al., J. Am. Chem. Soc., DOI: 10.1021/ja211042r (2012)