The flavin inhibitor diphenyleneiodonium renders Trichomonas vaginalis resistant to metronidazole, inhibits thioredoxin reductase and flavin reductase, and shuts off hydrogenosomal enzymatic pathways

摘要: Infections with the microaerophilic protozoan parasite Trichomonas vaginalis are commonly treated metronidazole, a 5-nitroimidazole drug. Metronidazole is selectively toxic to microaerophiles and anaerobes because reduction at drug's nitro group, which precondition for toxicity, occurs only quantitatively in these organisms. In our previous work we identified flavin enzyme thioredoxin reductase as an electron donor drugs T. observed that highly metronidazole-resistant cell lines lack activities. this study added inhibitor diphenyleneiodonium (DPI) cultures order test hypothesis metronidazole catalyzed by enzymes, e.g. reductase, intracellular free flavins. Indeed, within hours, DPI rendered insensitive concentrations high 1mM prevented formation of adducts proteins. Thioredoxin activity was absent from DPI-treated cells sharply decreased. addition, also upregulated expression antioxidant i.e. peroxidases superoxide dismutases, displayed fundamentally altered metabolism caused inactivation pyruvate:ferredoxin oxidoreductase (PFOR) concomitant upregulation lactate dehydrogenase (LDH) activity. Thus, disruption cellular mediated metabolic steps similar resistance induced vitro. Finally, present direct evidence increased enzymes dispensable acquiring metronidazole.