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.