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

Vincent, I.M. , Creek, D.J., Burgess, K., Woods, D.J., Burchmore, R.J.S. and Barrett, M.P. (2012) Untargeted metabolomics reveals a lack of synergy between nifurtimox and eflornithine against trypanosoma brucei. PLoS Neglected Tropical Diseases, 6(5), e1618. (doi: 10.1371/journal.pntd.0001618) (PMID:22563508) (PMCID:PMC3341325)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Vincent, Dr Isabel and Burchmore, Dr Richard and Creek, Dr Darren and Burgess, Dr Karl and Barrett, Professor Michael
• Authors: Vincent, I.M., Creek, D.J., Burgess, K., Woods, D.J., Burchmore, R.J.S., and Barrett, M.P.
• 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
• Published Online: 01 May 2012
• Copyright Holders: Copyright © 2012 The Authors
• First Published: First published in PLoS Neglected Tropical Diseases 6(5):e1618
• Publisher Policy: Reproduced under a Creative Commons License