Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain

Preston Sarah; Korhonen Pasi K.; Mouchiroud LaurentCornaglia MatteoMcGee Sean L.Young Neil D.Davis Rohan A.Crawford SimonNowell CameronAnsell Brendan R. E.Fisher Gillian M.Andrews Katherine T.Chang Bill C. H.Gijs Martin A. M.Sternberg Paul W.Auwerx JohanBaell JonathanHofmann AndreasJabbar AbdulGasser Robin B.

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Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain

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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.

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《The FASEB Journal》 |2017年第10期|4515-4532|共18页
作者
Preston Sarah; Korhonen Pasi K.; Mouchiroud LaurentCornaglia MatteoMcGee Sean L.Young Neil D.Davis Rohan A.Crawford SimonNowell CameronAnsell Brendan R. E.Fisher Gillian M.Andrews Katherine T.Chang Bill C. H.Gijs Martin A. M.Sternberg Paul W.Auwerx JohanBaell JonathanHofmann AndreasJabbar AbdulGasser Robin B.;
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作者单位

Griffith Univ, Griffith Inst Drug Discovery, Nathan, Qld, Australia;

Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3010, Australia;

Ecole Polytech Fed Lausanne, Lab Microsyst, Lausanne, SwitzerlandCALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USAEcole Polytech Fed Lausanne, Lab Integrat & Syst Physiol, Lausanne, SwitzerlandMonash Univ, Inst Pharmaceut Sci, Med Chem, Parkville, Vic, AustraliaDeakin Univ, Sch Med, Fac Hlth, Metab Res Unit,Metab Reprogramming Lab, Waurn Ponds, Vic, AustraliaUniv Melbourne, Sch Biosci, Parkville, Vic, AustraliaMonash Univ, Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic, Australia;

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正文语种英语
中图分类生物化学;
关键词
natural product; anthelmintic activity; transcriptomics; oxidative phosphorylation; nematode;

Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain

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