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

Ebiloma, G. U., Katsoulis, E., Igoli, J. O., Gray, A. I. and De Koning, H. P. (2018) Multi-target mode of action of a clerodane-type diterpenoid from Polyalthia longifolia targeting African trypanosomes. Scientific Reports, 8, 4613. (doi: 10.1038/s41598-018-22908-3) (PMID:29545637) (PMCID:PMC5854603)

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-hydroxycleroda-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 (0.4μg/ml) was trypanocidal, with its efect irreversible after only a brief exposure time (<1h). Fluorescence microscopic assessment of DNA confguration revealed severe cell cycle defects after 8h 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 antitrypanosomatid activity in our previous report.

• Item Type: Articles
• Additional Information: This work was funded by the Tertiary Education Trust Fund (TET Fund) being a PhD studentship grant to G.U.E.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ebiloma, Mr Godwin and De Koning, Professor Harry and Gray, Alexander
• Authors: Ebiloma, G. U., Katsoulis, E., Igoli, J. O., Gray, A. I., and De Koning, H. P.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Scientific Reports
• Publisher: Nature Research
• ISSN: 2045-2322
• ISSN (Online): 2045-2322
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Scientific Reports 8: 4613
• Publisher Policy: Reproduced under a Creative Commons License