Untargeted metabolomics reveals a lack of synergy between nifurtimox and eflornithine against Trypanosoma brucei.

A non-targeted metabolomics-based approach is presented that enables the study of pathways in response to drug action with the aim of defining the mode of action of trypanocides. Eflornithine, a polyamine pathway inhibitor, and nifurtimox, whose mode of action involves its metabolic activation, are...

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Autores principales:	Isabel M Vincent, Darren J Creek, Karl Burgess, Debra J Woods, Richard J S Burchmore, Michael P Barrett
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/83e3c421bbaa428ebc5866edd98e7162
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id	oai:doaj.org-article:83e3c421bbaa428ebc5866edd98e7162
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spelling	oai:doaj.org-article:83e3c421bbaa428ebc5866edd98e71622021-11-18T09:14:14ZUntargeted metabolomics reveals a lack of synergy between nifurtimox and eflornithine against Trypanosoma brucei.1935-27271935-273510.1371/journal.pntd.0001618https://doaj.org/article/83e3c421bbaa428ebc5866edd98e71622012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22563508/pdf/?tool=EBIhttps://doaj.org/toc/1935-2727https://doaj.org/toc/1935-2735A non-targeted metabolomics-based approach is presented that enables the study of pathways in response to drug action with the aim of defining the mode of action of trypanocides. Eflornithine, a polyamine pathway inhibitor, and nifurtimox, whose mode of action involves its metabolic activation, are currently used in combination as first line treatment against stage 2, CNS-involved, human African trypanosomiasis (HAT). Drug action was assessed using an LC-MS based non-targeted metabolomics approach. Eflornithine revealed the expected changes to the polyamine pathway as well as several unexpected changes that point to pathways and metabolites not previously described in bloodstream form trypanosomes, including a lack of arginase activity and N-acetylated ornithine and putrescine. Nifurtimox was shown to be converted to a trinitrile metabolite indicative of metabolic activation, as well as inducing changes in levels of metabolites involved in carbohydrate and nucleotide metabolism. However, eflornithine and nifurtimox failed to synergise anti-trypanosomal activity in vitro, and the metabolomic changes associated with the combination are the sum of those found in each monotherapy with no indication of additional effects. The study reveals how untargeted metabolomics can yield rapid information on drug targets that could be adapted to any pharmacological situation.Isabel M VincentDarren J CreekKarl BurgessDebra J WoodsRichard J S BurchmoreMichael P BarrettPublic Library of Science (PLoS)articleArctic medicine. Tropical medicineRC955-962Public aspects of medicineRA1-1270ENPLoS Neglected Tropical Diseases, Vol 6, Iss 5, p e1618 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
spellingShingle	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Isabel M Vincent Darren J Creek Karl Burgess Debra J Woods Richard J S Burchmore Michael P Barrett Untargeted metabolomics reveals a lack of synergy between nifurtimox and eflornithine against Trypanosoma brucei.
description	A non-targeted metabolomics-based approach is presented that enables the study of pathways in response to drug action with the aim of defining the mode of action of trypanocides. Eflornithine, a polyamine pathway inhibitor, and nifurtimox, whose mode of action involves its metabolic activation, are currently used in combination as first line treatment against stage 2, CNS-involved, human African trypanosomiasis (HAT). Drug action was assessed using an LC-MS based non-targeted metabolomics approach. Eflornithine revealed the expected changes to the polyamine pathway as well as several unexpected changes that point to pathways and metabolites not previously described in bloodstream form trypanosomes, including a lack of arginase activity and N-acetylated ornithine and putrescine. Nifurtimox was shown to be converted to a trinitrile metabolite indicative of metabolic activation, as well as inducing changes in levels of metabolites involved in carbohydrate and nucleotide metabolism. However, eflornithine and nifurtimox failed to synergise anti-trypanosomal activity in vitro, and the metabolomic changes associated with the combination are the sum of those found in each monotherapy with no indication of additional effects. The study reveals how untargeted metabolomics can yield rapid information on drug targets that could be adapted to any pharmacological situation.
format	article
author	Isabel M Vincent Darren J Creek Karl Burgess Debra J Woods Richard J S Burchmore Michael P Barrett
author_facet	Isabel M Vincent Darren J Creek Karl Burgess Debra J Woods Richard J S Burchmore Michael P Barrett
author_sort	Isabel M Vincent
title	Untargeted metabolomics reveals a lack of synergy between nifurtimox and eflornithine against Trypanosoma brucei.
title_short	Untargeted metabolomics reveals a lack of synergy between nifurtimox and eflornithine against Trypanosoma brucei.
title_full	Untargeted metabolomics reveals a lack of synergy between nifurtimox and eflornithine against Trypanosoma brucei.
title_fullStr	Untargeted metabolomics reveals a lack of synergy between nifurtimox and eflornithine against Trypanosoma brucei.
title_full_unstemmed	Untargeted metabolomics reveals a lack of synergy between nifurtimox and eflornithine against Trypanosoma brucei.
title_sort	untargeted metabolomics reveals a lack of synergy between nifurtimox and eflornithine against trypanosoma brucei.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/83e3c421bbaa428ebc5866edd98e7162
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Untargeted metabolomics reveals a lack of synergy between nifurtimox and eflornithine against Trypanosoma brucei.

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