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dc.contributor.authorTrochine, A
dc.contributor.authorCreek, DJ
dc.contributor.authorFaral-Tello, P
dc.contributor.authorBarrett, MP
dc.contributor.authorRobello, C
dc.date.accessioned2021-02-03T23:50:57Z
dc.date.available2021-02-03T23:50:57Z
dc.date.issued2014-05-01
dc.identifierpii: PNTD-D-13-02034
dc.identifier.citationTrochine, 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.
dc.identifier.issn1935-2735
dc.identifier.urihttp://hdl.handle.net/11343/258982
dc.description.abstractBACKGROUND: 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.
dc.languageEnglish
dc.publisherPUBLIC LIBRARY SCIENCE
dc.titleBenznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics
dc.typeJournal Article
dc.identifier.doi10.1371/journal.pntd.0002844
melbourne.affiliation.departmentBiochemistry and Molecular Biology
melbourne.affiliation.facultyMedicine, Dentistry & Health Sciences
melbourne.source.titlePLoS Neglected Tropical Diseases
melbourne.source.volume8
melbourne.source.issue5
dc.rights.licenseCC BY
melbourne.elementsid1050992
melbourne.contributor.authorCREEK, DARREN
dc.identifier.eissn1935-2735
melbourne.accessrightsOpen Access


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