Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain

Sarah Preston, Pasi K. Korhonen, Laurent Mouchiroud, Matteo Cornaglia, Sean L. McGee, Neil D. Young, Rohan A. Davis, Simon Crawford, Cameron Nowell, Brendan R.E. Ansell, Gillian M. Fisher, Katherine T. Andrews, Bill C.H. Chang, Martin A.M. Gijs, Paul W. Sternberg, Johan Auwerx, Jonathan Baell, Andreas Hofmann, Abdul Jabbar, Robin B. Gasser

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

Abstract

As a result of limited classes of anthelmintics and an over-reliance on chemical control, there is a great need to discover new compounds to combat drug resistance in parasitic nematodes. Here, we show that deguelin, a plant-derived rotenoid, selectively and potently inhibits the motility and development of nematodes, which supports its potential as a lead candidate for drug development. Furthermore, we demonstrate that deguelin treatment significantly increases gene transcription that is associated with energy metabolism, particularly oxidative phosphorylation and mitoribosomal protein production before inhibiting motility. Mitochondrial tracking confirmed enhanced oxidative phosphorylation. In accordance, real-time measurements of oxidative phosphorylation in response to deguelin treatment demonstrated an immediate decrease in oxygen consumption in both parasitic (Haemonchus contortus) and free-living (Caenorhabditis elegans) nematodes. Consequently, we hypothesize that deguelin is exerting its toxic effect on nematodes as a modulator of oxidative phosphorylation. This study highlights the dynamic biologic response of multicellular organisms to deguelin perturbation.

Original languageEnglish
Pages (from-to)4515-4532
Number of pages18
JournalThe FASEB Journal
Volume31
Issue number10
DOIs
Publication statusPublished - 1 Oct 2017

Keywords

  • Anthelmintic activity
  • Natural product
  • Nematode
  • Oxidative phosphorylation
  • Transcriptomics

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