Benzothiazinones: prodrugs that covalently modify the decaprenylphosphoryl-β-D-ribose 2'-epimerase DprE1 of Mycobacterium tuberculosis

Claudia Trefzer; Monica Rengifo-Gonzalez; Marlon J Hinner; Patricia Schneider; Vadim Makarov; Stewart T Cole; Kai Johnsson

doi:10.1021/ja106357w

Benzothiazinones: prodrugs that covalently modify the decaprenylphosphoryl-β-D-ribose 2'-epimerase DprE1 of Mycobacterium tuberculosis

J Am Chem Soc. 2010 Oct 6;132(39):13663-5. doi: 10.1021/ja106357w.

Authors

Claudia Trefzer¹, Monica Rengifo-Gonzalez, Marlon J Hinner, Patricia Schneider, Vadim Makarov, Stewart T Cole, Kai Johnsson

Affiliation

¹ New Medicines for Tuberculosis Consortium, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.

PMID: 20828197
DOI: 10.1021/ja106357w

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Catalytic Domain / drug effects
Molecular Conformation
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / enzymology
Prodrugs / chemical synthesis
Prodrugs / chemistry
Prodrugs / pharmacology*
Racemases and Epimerases / antagonists & inhibitors*
Racemases and Epimerases / chemistry
Stereoisomerism
Structure-Activity Relationship
Thiazines / chemical synthesis
Thiazines / chemistry
Thiazines / pharmacology*

Substances

Anti-Bacterial Agents
Prodrugs
Thiazines
Racemases and Epimerases