Benznidazole biotransformation and multiple targets in Trypanosoma cruzi revealed by metabolomics

Trochine, A., Creek, D. J., Faral-Tello, P., Barrett, M. P. and Robello, C. (2014) Benznidazole biotransformation and multiple targets in Trypanosoma cruzi revealed by metabolomics. PLoS Neglected Tropical Diseases, 8(5), e2844. (doi:10.1371/journal.pntd.0002844)

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Publisher's URL: http://dx.doi.org/10.1371/journal.pntd.0002844

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Creek, Dr Darren and Barrett, Professor Michael
Authors: Trochine, A., Creek, D. J., Faral-Tello, P., Barrett, M. P., and Robello, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Neglected Tropical Diseases
Publisher:Public Library of Science
ISSN:1935-2727
ISSN (Online):1935-2735
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in PLoS Neglected Tropical Diseases 8(5):e2844
Publisher Policy:Reproduced under a Creative Commons License

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