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- Title
Benznidazole Biotransformation and Multiple Targets in <i>Trypanosoma cruzi</i> Revealed by Metabolomics.
- Authors
Trochine, Andrea; Creek, Darren J.; Faral-Tello, Paula; Barrett, Michael P.; Robello, Carlos
- Abstract
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.
- Subjects
NITROIMIDAZOLES; TRYPANOSOMA; TRYPANOSOMATIDAE; METABOLOMICS; TROPICAL medicine
- Publication
PLoS Neglected Tropical Diseases, 2014, Vol 8, Issue 5, p1
- ISSN
1935-2727
- Publication type
Article
- DOI
10.1371/journal.pntd.0002844