| Abstract
| - Thiacetazone (TAZ) and ethionamide (ETA) are, respectively, thiourea- and thioamide-containing secondline antitubercular prodrugs for which there is an extensive clinical history of cross-resistance inMycobacterium tuberculosis. EtaA, a recently identified flavin-containing monooxygenase (FMO), isresponsible for the oxidative activation of ETA in M. tuberculosis. We report here that EtaA also oxidizesTAZ and identify a sulfinic acid and a carbodiimide as the isolable metabolites. Both of these metabolitesare derived from an initial sulfenic acid intermediate. Oxidation of TAZ by EtaA at basic pH favorsformation of the carbodiimide, whereas neutral or acidic conditions favor formation of the sulfinic acid.The same metabolites are formed from TAZ by human FMO1 and FMO3. The sulfenic acid andcarbodiimide metabolites, but not the sulfinic acid product, readily react with glutathione, the first toregenerate the parent drug and the second to give a glutathione adduct. These reactions may contributeto the antitubercular activity and/or toxicity of TAZ.
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