Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain

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 () and free-living () 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 the mitochondrial respiratory chain.

Natural Compounds from the Marine Brown Alga Caulocystis cephalornithos with Potent In Vitro-Activity against the Parasitic Nematode Haemonchus contortus

“…The use of transcriptomics and/or proteomics (cf. [17,[48][49][50]) might assist in testing this hypothesis and in elucidating the patho-molecular, -biochemical and/or -physiological mechanism(s).…”

“…Although there has been a major focus on synthetic compounds as anthelmintics [8,14], recent studies have shown that natural compounds from both terrestrial and marine environments have shown considerable promise [15][16][17][18][19] due to the diverse biologically active chemotypes in nature [20]. Current estimates indicate that there are >400,000 land plant species and ≥44,000 species of algae [21,22].…”

Selected α-pyrones from the plants Cryptocarya novoguineensis (Lauraceae) and Piper methysticum (Piperaceae) with activity against Haemonchus contortus in vitro

“…Over the last years, we have been working toward this goal, with an emphasis on the discovery of novel nematocidal or nematostatic compounds for medical chemistry optimisation and subsequent development (e.g., Preston et al, 2016, 2017a; Herath et al, 2017; Jiao et al, 2017). The Griffith Institute for Drug Discovery maintains multiple compound collections, including NatureBank which contains natural product extracts ( n = 10,000) and fractions ( n = 50,000) derived from plants, marine invertebrates and fungi as well as 30,000 archived biota samples linked to most of these samples (Camp et al, 2014).…”

Plant-Based Natural Products for the Discovery and Development of Novel Anthelmintics against Nematodes

“…It showed a strong anthelmintic activity (IC 50 = 14.8 µM) and low toxicity against human NFF cells (IC 50 > 50 µM) [75]. A more recent study suggested that deguelin exerts its anthelmintic activity via the mitochondrial respiratory chain by modulating oxidative phosphorylation [76].…”