Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics

Autores
Trochine, Andrea; Creek, Darren J.; Faral Tello, Paula; Barrett, Michael P.; Robello, Carlos
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Trochine, Andrea. Instituto Pasteur de Montevideo; Uruguay. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Patagonia Norte. Instituto de Investigación en Biodiversidad y Medioambiente; Argentina
Fil: Creek, Darren J.. University Of Glasgow; Reino Unido. The University Of Melbourne; Australia
Fil: Faral Tello, Paula. Instituto Pasteur de Montevideo; Uruguay
Fil: Barrett, Michael P.. University Of Glasgow; Reino Unido
Fil: Robello, Carlos. Instituto Pasteur de Montevideo; Uruguay. Universidad de la Republica; Uruguay
Materia
BENZNIDAZOLE
TRYPANOSOMA CRUZI
CHAGAS
METABOLOMICS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/11967
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by MetabolomicsTrochine, AndreaCreek, Darren J.Faral Tello, PaulaBarrett, Michael P.Robello, CarlosBENZNIDAZOLETRYPANOSOMA CRUZICHAGASMETABOLOMICShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Background 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.Fil: Trochine, Andrea. Instituto Pasteur de Montevideo; Uruguay. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Patagonia Norte. Instituto de Investigación en Biodiversidad y Medioambiente; ArgentinaFil: Creek, Darren J.. University Of Glasgow; Reino Unido. The University Of Melbourne; AustraliaFil: Faral Tello, Paula. Instituto Pasteur de Montevideo; UruguayFil: Barrett, Michael P.. University Of Glasgow; Reino UnidoFil: Robello, Carlos. Instituto Pasteur de Montevideo; Uruguay. Universidad de la Republica; UruguayPublic Library Of Science2014-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/11967Trochine, Andrea; Creek, Darren J.; Faral Tello, Paula; Barrett, Michael P.; Robello, Carlos; Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics; Public Library Of Science; Neglected Tropical Diseases; 8; 5; 5-2014; 1-151935-2735enginfo:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0002844info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pntd.0002844info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:21:21Zoai:ri.conicet.gov.ar:11336/11967instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:21:22.215CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics
title Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics
spellingShingle Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics
Trochine, Andrea
BENZNIDAZOLE
TRYPANOSOMA CRUZI
CHAGAS
METABOLOMICS
title_short Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics
title_full Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics
title_fullStr Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics
title_full_unstemmed Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics
title_sort Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics
dc.creator.none.fl_str_mv Trochine, Andrea
Creek, Darren J.
Faral Tello, Paula
Barrett, Michael P.
Robello, Carlos
author Trochine, Andrea
author_facet Trochine, Andrea
Creek, Darren J.
Faral Tello, Paula
Barrett, Michael P.
Robello, Carlos
author_role author
author2 Creek, Darren J.
Faral Tello, Paula
Barrett, Michael P.
Robello, Carlos
author2_role author
author
author
author
dc.subject.none.fl_str_mv BENZNIDAZOLE
TRYPANOSOMA CRUZI
CHAGAS
METABOLOMICS
topic BENZNIDAZOLE
TRYPANOSOMA CRUZI
CHAGAS
METABOLOMICS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
Fil: Trochine, Andrea. Instituto Pasteur de Montevideo; Uruguay. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Patagonia Norte. Instituto de Investigación en Biodiversidad y Medioambiente; Argentina
Fil: Creek, Darren J.. University Of Glasgow; Reino Unido. The University Of Melbourne; Australia
Fil: Faral Tello, Paula. Instituto Pasteur de Montevideo; Uruguay
Fil: Barrett, Michael P.. University Of Glasgow; Reino Unido
Fil: Robello, Carlos. Instituto Pasteur de Montevideo; Uruguay. Universidad de la Republica; Uruguay
description 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.
publishDate 2014
dc.date.none.fl_str_mv 2014-05
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/11967
Trochine, Andrea; Creek, Darren J.; Faral Tello, Paula; Barrett, Michael P.; Robello, Carlos; Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics; Public Library Of Science; Neglected Tropical Diseases; 8; 5; 5-2014; 1-15
1935-2735
url http://hdl.handle.net/11336/11967
identifier_str_mv Trochine, Andrea; Creek, Darren J.; Faral Tello, Paula; Barrett, Michael P.; Robello, Carlos; Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics; Public Library Of Science; Neglected Tropical Diseases; 8; 5; 5-2014; 1-15
1935-2735
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0002844
info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pntd.0002844
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library Of Science
publisher.none.fl_str_mv Public Library Of Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.48226

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