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FASEB J. 2017 Oct;31(10):4515-4532. doi: 10.1096/fj.201700288R. Epub 2017 Jul 7.

Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain.

Author information

1
Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia.
2
Faculty of Science and Technology, Federation University, Ballarat, Victoria, Australia.
3
Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
4
Laboratory of Microsystems, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
5
Metabolic Research Unit, Metabolic Reprogramming Laboratory, School of Medicine, Faculty of Health, Deakin University, Waurn Ponds, Victoria, Australia.
6
Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
7
School of Biosciences, University of Melbourne, Parkville, Victoria, Australia.
8
Drug Discovery Biology, Monash University Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
9
Yourgene Bioscience, Taipei, Taiwan.
10
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
11
Medicinal Chemistry, Monash University Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
12
Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia; robinbg@unimelb.edu.au.

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.-Preston, S., Korhonen, P. K., Mouchiroud, L., Cornaglia, M., McGee, S. L., Young, N. D., Davis, R. A., Crawford, S., Nowell, C., Ansell, B. R. E., Fisher, G. M., Andrews, K. T., Chang, B. C. H., Gijs, M. A. M., Sternberg, P. W., Auwerx, J., Baell, J., Hofmann, A., Jabbar, A., Gasser, R. B. Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain.

KEYWORDS:

anthelmintic activity; natural product; nematode; oxidative phosphorylation; transcriptomics

PMID:
28687609
DOI:
10.1096/fj.201700288R
[Indexed for MEDLINE]

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