Examination of the Mode of Action of the Almiramide Family of Natural Products against the Kinetoplastid Parasite Trypanosoma brucei

TitleExamination of the Mode of Action of the Almiramide Family of Natural Products against the Kinetoplastid Parasite Trypanosoma brucei
Publication TypeJournal Article
Year of Publication2013
AuthorsSanchez LM, Knudsen GM, Helbig C, De Muylder G, Mascuch SM, Mackey ZB, Gerwick L, Clayton C, McKerrow JH, Linington RG
JournalJournal of Natural Products
Volume76
Pagination630-641
Date Published2013/04
Type of ArticleArticle
ISBN Number0163-3864
Accession NumberWOS:000318264700021
Keywordsglycosomes; hearing-loss; human african trypanosomiasis; identification; lead compounds; mass-spectrometry; membrane; proteins; shotgun proteomics; sleeping sickness
Abstract

Almiramide C is a marine natural product with low micromolar activity against Leishmania donovani, the causative agent of leishmaniasis. We have now shown that almiramide C is also active against the related parasite Ttypanosoma brucei, the causative agent of human African trypanosomiasis. A series of activity-based probes have been synthesized to explore both the molecular target of this compound series in T. brucei lysates and site localization through epifluorescence microscopy. These target identification studies indicate that the almiramides likely perturb glycosomal function through disruption of membrane assembly machinery. Glycosomes, which are organelles specific to kinetoplastid parasites, house the first seven steps of glycolysis and have been shown to be essential for parasite survival in the bloodstream stage. There are currently no reported smallmolecule disruptors of glycosome function, making the almiramides unique molecular probes for this understudied parasitespecific organelle. Additionally, examination of toxicity in an in vivo zebrafish model has shown that these compounds have little effect on organism development, even at high concentrations, and has uncovered a potential side effect through localization of fluorescent derivatives to zebrafish neuromast cells. Combined, these results further our understanding of the potential value of this lead series as development candidates against T. brucei.

DOI10.1021/np300834q
Short TitleJ. Nat. Prod.
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