Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain
- Creators
- Preston, Sarah
- Korhonen, Pasi K.
- Mouchiroud, Laurent
- Cornaglia, Matteo
- McGee, Sean L.
- Young, Neil D.
- Davis, Rohan A.
- Crawford, Simon
- Nowell, Cameron
- Ansell, Brendan R. E.
- Fisher, Gillian M.
- Andrews, Katherine T.
- Chang, Bill C. H.
- Gijs, Martin A. M.
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Sternberg, Paul W.
- Auwerx, Johan
- Baell, Jonathan
- Hofmann, Andreas
- Jabbar, Abdul
- Gasser, Robin B.
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 mito-ribosomal 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.
Additional Information
© 2017 FASEB. Received April 5, 2017; Accepted June 12, 2017; Published online before print July 7, 2017. 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 École Polytechnique Fédérale de Lausanne, and the Gebert Rüf Stiftung (GRS-025/16) and the AgingX program of the Swiss Initiative for Systems Biology (to J.A. and L.H.). 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/compoundsaustralia) 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. Author Contributions: S. Preston, L. Mouchiroud, S. L. McGee, K. T. Andrews, B. Chang, M.A. M. Gijs, P. W. Sternberg, J. Auwerx, J. Baell, A. Hofmann, A. Jabbar, and R. B. Gasser designed research; S. Preston, P. K. Korhonen, L. Mouchiroud, M. Cornaglia, and B. R. E.Ansell analyzed data; S. Preston, L.Mouchiroud, M. Cornaglia, S. L.McGee, N. D. Young, S. Crawford, and G. M. Fisher performed research; S. Preston, L. Mouchiroud, andR. B. Gasser wrote thepaper; R. A. Davis contributed reagents; and C. Nowell developed software to analyze data.Attached Files
Supplemental Material - Supplemental_Table1.xlsx
Supplemental Material - Supplemental_Table2.xlsx
Supplemental Material - Supplemental_Table3.xlsx
Supplemental Material - Supplemental_Table4.xlsx
Supplemental Material - Supplemental_Table5.xlsx
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Additional details
- Eprint ID
- 79128
- DOI
- 10.1096/fj.201700288R
- Resolver ID
- CaltechAUTHORS:20170717-103000121
- Australian Research Council
- National Health and Medical Research Council (NHMRC)
- Medicines for Malaria Venture
- Yourgene Bioscience
- University of Melbourne
- École Polytechnique Fédérale de Lausanne
- Gebert Rüf Stiftung
- GRS-025/16
- Swiss Initiative for Systems Biology
- European Research Council (ERC)
- 320404
- Griffith University
- Created
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2017-07-17Created from EPrint's datestamp field
- Updated
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2021-11-15Created from EPrint's last_modified field