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.
Highlights
Human African trypanosomiasis (HAT) is a parasitic infection in sub-Saharan Africa transmitted by tsetse flies
This indicated that eflornithine, which inhibits polyamine biosynthesis [9,10] and subsequently trypanothione biosynthesis, would synergise with nifurtimox as result of a reduced ability of cells to deal with oxidative stress
The data that lead to the conclusion that nifurtimox causes oxidative stress is inconclusive [7] and recent evidence shows that nifurtimox is activated upon metabolism to an open chain nitrile [11] and that this nitrile is as toxic as the parent drug
Summary
Human African trypanosomiasis (HAT) is a parasitic infection in sub-Saharan Africa transmitted by tsetse flies. In trypanosomes polyamines serve an unusual role in combining with glutathione to create the metabolite trypanothione [8], which carries out many of the cellular roles usually attributed to glutathione in other cell types, including protection against oxidative stress. This indicated that eflornithine, which inhibits polyamine biosynthesis [9,10] and subsequently trypanothione biosynthesis, would synergise with nifurtimox as result of a reduced ability of cells to deal with oxidative stress. Isobologram analysis indicated that the two drugs were not synergistic in vitro [13]
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