Antiparasitic prodrug nifurtimox: revisiting its activation mechanism

Evaluation of: Hall BS, Bot C, Wilkinson SR. Nifurtimox activation by trypanosomal type I nitroreductases generates cytotoxic nitrile metabolites. J. Biol. Chem. 286, 13088-13095 (2011). The prodrug nifurtimox has been one of the pharmacologic alternatives to treat Chagas disease and currently forms part of a combinational therapy to treat West African trypanosomiasis. Despite this, nifurtimox's mechanism of action is only partially understood and has been related to induction of oxidative stress in the target cell. An alternative mechanism involving reductive activation by a eukaryotic type I nitroreductase has been described. Bloodstream form Trypanosoma brucei overexpressing enzymes, proposed to metabolize nifurtimox, were generated and only cells with elevated levels of the nitroreductase displayed altered susceptibility to the drug, implying that it has a key role in drug action. Reduction of nifurtimox by trypanosomal type I nitroreductases was shown to be insensitive to oxygen and yielded a product characterized by liquid chromatography/mass spectrometry as an unsaturated open chain nitrile. This nitrile inhibited both parasite and mammalian cell growth at equivalent concentrations, in marked contrast to the parental prodrug. These studies indicated that nifurtimox selectivity against T. brucei could be the result of the expression of a parasite-encoded type I nitroreductase.