Metabolomics and lipidomics reveal perturbation of sphingolipid metabolism by a novel anti-trypanosomal 3-(oxazolo[4,5-b]pyridine-2-yl)anilide

Daniel Stoessel, Cameron J. Nowell, Amy J. Jones, Lori Ferrins, Katherine M. Ellis, Jennifer Riley, Raphael Rahmani, Kevin D. Read, Malcolm J. McConville, Vicky M. Avery, Jonathan B. Baell, Darren J. Creek

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Abstract

Introduction: Trypanosoma brucei is the causative agent of human African trypanosomiasis, which is responsible for thousands of deaths every year. Current therapies are limited and there is an urgent need to develop new drugs. The anti-trypanosomal compound, 3-(oxazolo[4,5-b]pyridine-2-yl)anilide (OXPA), was initially identified in a phenotypic screen and subsequently optimized by structure–activity directed medicinal chemistry. It has been shown to be non-toxic and to be active against a number of trypanosomatid parasites. However, nothing is known about its mechanism of action. Objective: Here, we have utilized an untargeted metabolomics approach to investigate the biochemical effects and potential mode of action of this compound in T. brucei. Methods: Total metabolite extracts were analysed by HILIC-chromatography coupled to high resolution mass spectrometry. Results: Significant accumulation of ceramides was observed in OXPA-treated T. brucei. To further understand drug-induced changes in lipid metabolism, a lipidomics method was developed which enables the measurement of hundreds of lipids with high throughput and precision. The application of this LC–MS based approach to cultured bloodstream-form T. brucei putatively identified over 500 lipids in the parasite including glycerophospholipids, sphingolipids and fatty acyls, and confirmed the OXPA-induced accumulation of ceramides. Labelling with BODIPY-ceramide further confirmed the ceramide accumulation following drug treatment. Conclusion: These findings clearly demonstrate perturbation of ceramide metabolism by OXPA and indicate that the sphingolipid pathway is a promising drug target in T. brucei.

Original languageEnglish
Article number126
Number of pages14
JournalMetabolomics
Volume12
Issue number7
DOIs
Publication statusPublished - 1 Jul 2016

Keywords

  • Human African trypanosomiasis
  • Lipidomics
  • Metabolomics
  • Sphingolipid metabolism
  • Trypanosoma brucei

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