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)
|
Text
95238.pdf - Published Version Available under License Creative Commons Attribution. 1MB |
Publisher's URL: http://dx.doi.org/10.1371/journal.pntd.0002844
Abstract
<b>Background</b><p></p> 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.<p></p> <b>Methodology/Principal findings</b><p></p> 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.<p></p> <b>Conclusions/significance</b><p></p> 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 > School of Infection & Immunity |
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 |
University Staff: Request a correction | Enlighten Editors: Update this record