Format

Send to

Choose Destination
PLoS Negl Trop Dis. 2014 May 22;8(5):e2844. doi: 10.1371/journal.pntd.0002844. eCollection 2014 May.

Benznidazole biotransformation and multiple targets in Trypanosoma cruzi revealed by metabolomics.

Author information

1
Unidad de Biología Molecular, Institut Pasteur de Montevideo, Montevideo, Uruguay.
2
The Wellcome Trust Centre for Molecular Parasitology, Institute for Infection, Immunity and Inflammation and Glasgow Polyomics, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
3
The Wellcome Trust Centre for Molecular Parasitology, Institute for Infection, Immunity and Inflammation and Glasgow Polyomics, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
4
Unidad de Biología Molecular, Institut Pasteur de Montevideo, Montevideo, Uruguay; Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.

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.

PMID:
24853684
PMCID:
PMC4031082
DOI:
10.1371/journal.pntd.0002844
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center