Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics
Web of Science
AuthorTrochine, A; Creek, DJ; Faral-Tello, P; Barrett, MP; Robello, C
Source TitlePLoS Neglected Tropical Diseases
PublisherPUBLIC LIBRARY SCIENCE
University of Melbourne Author/sCREEK, DARREN
AffiliationBiochemistry and Molecular Biology
Document TypeJournal Article
CitationsTrochine, A., Creek, D. J., Faral-Tello, P., Barrett, M. P. & Robello, C. (2014). Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics. PLOS NEGLECTED TROPICAL DISEASES, 8 (5), https://doi.org/10.1371/journal.pntd.0002844.
Access StatusOpen Access
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.
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