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 RE Ansell; Gillian M Fisher; Katherine T Andrews; Bill CH Chang; Martin AM Gijs; Paul W Sternberg; Johan Auwerx; Jonathan Baell; Andreas Hofmann; Abdul Jabbar; Robin B Gasser

Journal article

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 RE Ansell, Gillian M Fisher, Katherine T Andrews, Bill CH Chang, Martin AM Gijs, Paul W Sternberg, Johan Auwerx, Jonathan Baell, Andreas Hofmann, Abdul Jabbar, Robin B Gasser

FASEB JOURNAL | WILEY | Published : 2017

DOI: 10.1096/fj.201700288R

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..

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University of Melbourne Researchers

Bill Chang Author Veterinary Biosciences

Abdul Jabbar Author Veterinary Biosciences

Robin Gasser Author Veterinary Biosciences

Pasi Korhonen Author Veterinary Biosciences

Neil Young Author Veterinary Biosciences

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Grants

Awarded by Gebert Ruf Stiftung

Awarded by EU Ideas Program

Funding Acknowledgements

This study was supported by the Australian Research Council and the National Health and Medical Research Council (NHMRC) of Australia, as well as by the Medicines for Malaria Venture, Yourgene Bioscience, the University of Melbourne (to R.B.G. S.P., A.J., J.B., B.C.H.C., and A.H.), the Ecole Polytechnique Federale de Lausanne, and the Gebert Ruf Stiftung (GRS-025/16) and the AgingX program of the Swiss Initiative for Systems Biology (to J.A. and L.M.). Some work was supported by the EU Ideas Program (ERC-2012-AdG-320404; to M.A.M.G and M.C.). G.M.F. was supported by a postdoctoral fellowship and a new researcher grant from Griffith University. P.K.K. was supported by an early career research fellowship, and N.D.Y. by a career development fellowship (CDF1) from NHMRC. Funding bodies played no role in the design of the study or collection, analysis, or interpretation of data, or in the writing of the manuscript. The authors thank Compounds Australia (http://www.griffith.edu.au/science-aviation/compounds-australia) for access to the Davis open-access natural product library, which forms part of the Open Access Compound Collection. The authors declare no conflicts of interest.