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

Sci Rep. 2018 Mar 15;8(1):4613. doi: 10.1038/s41598-018-22908-3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diterpenes, Clerodane / pharmacology*
  • Plant Extracts / pharmacology*
  • Plant Leaves / chemistry
  • Polyalthia / chemistry*
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma brucei brucei / drug effects*
  • Trypanosoma brucei brucei / growth & development
  • Trypanosomiasis, African / drug therapy*
  • Trypanosomiasis, African / parasitology

Substances

  • Diterpenes, Clerodane
  • Plant Extracts
  • Trypanocidal Agents