Bioactivation of antituberculosis thioamide and thiourea prodrugs by bacterial and mammalian flavin monooxygenases.
The thioamide and thiourea class of antituberculosis agents encompasses prodrugs that are oxidatively converted to their active forms by the flavin monooxygenase EtaA of Mycobacterium tuberculosis. Reactive intermediates produced in the EtaA-catalyzed transformations of ethionamide and prothionamide result in NAD(+)/NADH adducts that inhibit the enoyl CoA reductase InhA, the ultimate target of these drugs. In the case of thiacetazone and isoxyl, EtaA produces electrophilic metabolites that mediate the antibacterial activity of these agents. The oxidation of the thioamide/thiourea drugs by the human flavin monooxygenases yields similar reactive metabolites that contribute to the toxicities associated with these second line antituberculosis drugs.
Nishida
Clinton R
CR
Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, CA 94158-2517, USA.
Ortiz de Montellano
Paul R
PR
D000995:Antitubercular Agents / Q000493:pharmacokinetics*; D001711:Biotransformation; D005415:Flavins / Q000378:metabolism*; D006801:Humans; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000493:pharmacokinetics*; D013854:Thioamides / Q000493:pharmacokinetics*; D013890:Thiourea / Q000493:pharmacokinetics*
D000995:Antitubercular Agents; D005415:Flavins; D011355:Prodrugs; D013854:Thioamides; D006899:Mixed Function Oxygenases; D013890:Thiourea