Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics

Background:the first line treatment for chagas disease,a neglected tropical disease caused by the protozoan parasite trypanosoma cruzi,involves administration of benznidazole (bzn). bzn is a 2-nitroimidazole pro-drug which requires nitroreduction to become active,although its mode of action is not fully understood. in the present work we used a non-targeted ms-based metabolomics approach to study the metabolic response of t. cruzi to bzn.methodology/principal findings:parasites treated with bzn were minimally altered compared to untreated trypanosomes,although the redox active thiols trypanothione,homotrypanothione and cysteine were significantly diminished in abundance post-treatment. in addition,multiple bzn-derived metabolites were detected after treatment. these metabolites included reduction products,fragments and covalent adducts of reduced bzn linked to each of the major low molecular weight thiols: trypanothione,glutathione,γ-glutamylcysteine,glutathionylspermidine,cysteine and ovothiol a. bzn products known to be generated in vitro by the unusual trypanosomal nitroreductase,tcntri,were found within the parasites,but low molecular weight adducts of glyoxal,a proposed toxic end-product of ntri bzn metabolism,were not detected.conclusions/significance:our data is indicative of a major role of the thiol binding capacity of bzn reduction products in the mechanism of bzn toxicity against t. cruzi. © 2014 trochine et al.