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Bioactivation of antituberculosis thioamide and thiourea prodrugs by bacterial and mammalian flavin monooxygenases

Authors
Journal
Chemico-Biological Interactions
0009-2797
Publisher
Elsevier
Publication Date
Volume
192
Identifiers
DOI: 10.1016/j.cbi.2010.09.015
Keywords
  • Antituberculosis Drugs
  • Drug Metabolism
  • Flavin Monooxygenases
  • Thiacetazone
  • Ethionamide
  • Isoxyl

Abstract

Abstract 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.

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