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Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain

Preston, Sarah and Korhonen, Pasi K. and Mouchiroud, Laurent and Cornaglia, Matteo and McGee, Sean L. and Young, Neil D. and Davis, Rohan A. and Crawford, Simon and Nowell, Cameron and Ansell, Brendan R. E. and Fisher, Gillian M. and Andrews, Katherine T. and Chang, Bill C. H. and Gijs, Martin A. M. and Sternberg, Paul W. and Auwerx, Johan and Baell, Jonathan and Hofmann, Andreas and Jabbar, Abdul and Gasser, Robin B. (2017) Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain. FASEB Journal, 31 (10). pp. 4515-4532. ISSN 0892-6638. https://resolver.caltech.edu/CaltechAUTHORS:20170717-103000121

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1096/fj.201700288RDOIArticle
http://www.fasebj.org/content/31/10/4515PublisherArticle
http://www.fasebj.org/content/31/10/4515/suppl/DC1PublisherSupplemental Data
ORCID:
AuthorORCID
Sternberg, Paul W.0000-0002-7699-0173
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.
Funders:
Funding AgencyGrant Number
Australian Research CouncilUNSPECIFIED
National Health and Medical Research Council (NHMRC)UNSPECIFIED
Medicines for Malaria VentureUNSPECIFIED
Yourgene BioscienceUNSPECIFIED
University of MelbourneUNSPECIFIED
École Polytechnique Fédérale de LausanneUNSPECIFIED
Gebert Rüf StiftungGRS-025/16
Swiss Initiative for Systems BiologyUNSPECIFIED
European Research Council (ERC)320404
Griffith UniversityUNSPECIFIED
Subject Keywords:natural product; anthelmintic activity; transcriptomics; oxidative phosphorylation; nematode
Issue or Number:10
Record Number:CaltechAUTHORS:20170717-103000121
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170717-103000121
Official Citation: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, and Robin B. Gasser Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain FASEB J October 2017 31:4515-4532; published ahead of print July 7, 2017, doi:10.1096/fj.201700288R.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:79128
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:17 Jul 2017 19:17
Last Modified:03 Oct 2019 18:16

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