Multi-target mode of action of a Clerodane-type diterpenoid from Polyalthia longifolia targeting African trypanosomes

Godwin U. Ebiloma, Evangelos Katsoulis, John O. Igoli, Alexander I. Gray, Harry P. De Koning

Research output: Contribution to journalArticle

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Abstract

Natural products have made remarkable contributions to drug discovery and therapy. In this work we exploited various biochemical approaches to investigate the mode of action of 16-α-hydroxy-cleroda-3,13 (14)-Z-dien-15,16-olide (HDK-20), which we recently isolated from Polyalthia longifolia, on Trypanosoma brucei bloodstream trypomastigotes. HDK20 at concentrations ≥ EC50 (0.4 μg/ml) was trypanocidal, with its effect irreversible after only a brief exposure time (<1 h). Fluorescence microscopic assessment of DNA configuration revealed severe cell cycle defects after 8 h of incubation with the compound, the equivalent of a single generation time. This was accompanied by DNA fragmentation as shown by Terminal deoxynucleotidyl transferase dUTP Nick-End Labelling (TUNEL) assays. HDK-20 also induced a fast and profound depolarisation of the parasites' mitochondrial membrane potential and depleted intracellular ATP levels of T. brucei. Overall, HDK20 showed a multi-target mechanism of action, which provides a biochemical explanation for the promising anti-trypanosomatid activity in our previous report.

Original languageEnglish
Article number4613
Pages (from-to)1-9
Number of pages9
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 15 Mar 2018

Keywords

  • parasite physiology
  • target identification

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