Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain
- Preston, Sarah, Korhonen, Pasi, Mouchiroud, Laurent, Cornaglia, Matteo, McGee, Sean, Young, Neil, Davis, Rohan, Crawford, Simon, Nowell, Cameron, Ansell, Brendan, Fisher, Gillian, Andrews, Katherine, Chang, Bill, Gijs, Martin, Sternberg, Paul, Auwerx, Johan, Baell, Jonathan, Hofmann, Andreas, Jabbar, Abdul, Gasser, Robin
- Authors: Preston, Sarah , Korhonen, Pasi , Mouchiroud, Laurent , Cornaglia, Matteo , McGee, Sean , Young, Neil , Davis, Rohan , Crawford, Simon , Nowell, Cameron , Ansell, Brendan , Fisher, Gillian , Andrews, Katherine , Chang, Bill , Gijs, Martin , Sternberg, Paul , Auwerx, Johan , Baell, Jonathan , Hofmann, Andreas , Jabbar, Abdul , Gasser, Robin
- Date: 2017
- Type: Text , Journal article
- Relation: FASEB Journal Vol. 31, no. 10 (2017), p. 4515-4532
- Full Text: false
- Reviewed:
- Description: 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. © FASEB.
Identification of fromiamycalin and halaminol A from Australian marine sponge extracts with anthelmintic activity against haemonchus contortus
- Herath, Dilrukshi, Preston, Sarah, Jabbar, Abdul, Garcia-Bustos, Jose, Taki, Aya, Addison, Russell, Hayes, Sasha, Beattie, Karren, McGee, Sean, Martin, Sheree, Ekin, Merrick, Hooper, John, Chang, Bill, Hofmann, Andreas, Davis, Rohan, Gasser, Robin
- Authors: Herath, Dilrukshi , Preston, Sarah , Jabbar, Abdul , Garcia-Bustos, Jose , Taki, Aya , Addison, Russell , Hayes, Sasha , Beattie, Karren , McGee, Sean , Martin, Sheree , Ekin, Merrick , Hooper, John , Chang, Bill , Hofmann, Andreas , Davis, Rohan , Gasser, Robin
- Date: 2019
- Type: Text , Journal article
- Relation: Marine Drugs Vol. 17, no. 11 (Nov 2019), p. 14
- Full Text:
- Reviewed:
- Description: There is an urgent need to discover and develop new anthelmintics for the treatment of parasitic nematodes of veterinary importance to circumvent challenges linked to drug resistant parasites. Being one of the most diverse natural ecosystems, the marine environment represents a rich resource of novel chemical entities. This study investigated 2000 extracts from marine invertebrates, collected from Australian waters, for anthelmintic activity. Using a well-established in vitro bioassay, these extracts were screened for nematocidal activity against Haemonchus contortus - a socioeconomically important parasitic nematode of livestock animals. Extracts (designated Mu-1, Ha-1 and Ha-2) from two marine sponges (Monanchora unguiculata and Haliclona sp.) each significantly affected larvae of H. contortus. Individual extracts displayed a dose-dependent inhibition of both the motility of exsheathed third-stage larvae (xL3s) and the development of xL3s to fourth-stage larvae (L4s). Active fractions in each of the three extracts were identified using bioassay-guided fractionation. From the active fractions from Monanchora unguiculata, a known pentacyclic guanidine alkaloid, fromiamycalin (1), was purified. This alkaloid was shown to be a moderately potent inhibitor of L4 development (half-maximum inhibitory concentration (IC50) = 26.6 +/- 0.74 mu M) and L4 motility (IC50 = 39.4 +/- 4.83 mu M), although it had a relatively low potency at inhibiting of xL3 motility (IC50 >= 100 mu M). Investigation of the active fractions from the two Haliclona collections led to identification of a mixture of amino alcohol lipids, and, subsequently, a known natural product halaminol A (5). Anthelmintic profiling showed that 5 had limited potency at inhibiting larval development and motility. These data indicate that fromiamycalin, other related pentacyclic guanidine alkaloids and/or halaminols could have potential as anthelmintics following future medicinal chemistry efforts.
- Authors: Herath, Dilrukshi , Preston, Sarah , Jabbar, Abdul , Garcia-Bustos, Jose , Taki, Aya , Addison, Russell , Hayes, Sasha , Beattie, Karren , McGee, Sean , Martin, Sheree , Ekin, Merrick , Hooper, John , Chang, Bill , Hofmann, Andreas , Davis, Rohan , Gasser, Robin
- Date: 2019
- Type: Text , Journal article
- Relation: Marine Drugs Vol. 17, no. 11 (Nov 2019), p. 14
- Full Text:
- Reviewed:
- Description: There is an urgent need to discover and develop new anthelmintics for the treatment of parasitic nematodes of veterinary importance to circumvent challenges linked to drug resistant parasites. Being one of the most diverse natural ecosystems, the marine environment represents a rich resource of novel chemical entities. This study investigated 2000 extracts from marine invertebrates, collected from Australian waters, for anthelmintic activity. Using a well-established in vitro bioassay, these extracts were screened for nematocidal activity against Haemonchus contortus - a socioeconomically important parasitic nematode of livestock animals. Extracts (designated Mu-1, Ha-1 and Ha-2) from two marine sponges (Monanchora unguiculata and Haliclona sp.) each significantly affected larvae of H. contortus. Individual extracts displayed a dose-dependent inhibition of both the motility of exsheathed third-stage larvae (xL3s) and the development of xL3s to fourth-stage larvae (L4s). Active fractions in each of the three extracts were identified using bioassay-guided fractionation. From the active fractions from Monanchora unguiculata, a known pentacyclic guanidine alkaloid, fromiamycalin (1), was purified. This alkaloid was shown to be a moderately potent inhibitor of L4 development (half-maximum inhibitory concentration (IC50) = 26.6 +/- 0.74 mu M) and L4 motility (IC50 = 39.4 +/- 4.83 mu M), although it had a relatively low potency at inhibiting of xL3 motility (IC50 >= 100 mu M). Investigation of the active fractions from the two Haliclona collections led to identification of a mixture of amino alcohol lipids, and, subsequently, a known natural product halaminol A (5). Anthelmintic profiling showed that 5 had limited potency at inhibiting larval development and motility. These data indicate that fromiamycalin, other related pentacyclic guanidine alkaloids and/or halaminols could have potential as anthelmintics following future medicinal chemistry efforts.
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