New ways to target the deadly parasite Echinococcus multilocularis

Ritler, Dominic (2020). New ways to target the deadly parasite Echinococcus multilocularis (Unpublished). (Dissertation, Institut für Parasitologie IPA, Vetsuisse)

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Alveolar echinococcosis (AE) is a zoonotic disease caused by the metacestode stage of the fox tapeworm Echinococcus multilocularis. AE is endemic in the Northern hemisphere and lethal if untreated. The only currently available treatment is complete resection by surgery and chemotherapeutic follow up. Unfortunately, surgery is often no option due to the long asymptomatic course of AE causing a late diagnosis. Despite efforts made to find new compounds, no new drugs have reached to the market in the last decades. This is also true for treatment options against the adult stage of the parasite (e.g. in dogs), which is not clinically important, but highly relevant in terms of transmission to humans. Praziquantel is the only drug in use against adult cestodes and is also and highly effective also against other cestodes and trematodes. Thus, development of praziquantel resistance could have serious consequences. With this in mind, the major goal of this thesis was to identify novel drugs and potential drug targets for the treatment of infections with the adult and metacestode stage of E. multilocularis.
In terms of the adult stage, we established a novel semi-automated motility-based in vitro drug screening technique. E. multilocularis protoscoleces were used as a model for adult cestodes, utilizing protoscolex movement as a quantitative readout. The assay was validated using a number of anthelminthic drugs, and we identified one compound, MMV665807, which was obtained from the open access MMV (Medicines for Malaria Venture) Malaria box, as a potential hit that strongly impaired motility and viability of protoscoleces.
In terms of contributing to drug development against the metacestode stage, we investigated the proteomic and metabolic footprint of parasites cultured in vitro through the use of mass spectrometry and magnetic resonance spectroscopy. We found that fermentative end products such as acetate, alanine, lactate, and succinate were released by the parasite indicating an active anaerobic fermentation. To generate energy, the parasite uses the malate dismutation pathway and the NADHfumarate reductase system, both of which are not present in humans and therefore represent potentially interesting drug targets. We found that, besides glucose, also the amino acid threonine is highly consumed by metacestodes. In Echinococcus, threonine degradation might take place via threonine dehydrogenase, which in humans is only expressed as a pseudogene, and therefore could also represent an interesting drug target provided suitable inhibitors are identified. We also identified other potential targets involved in the transport of nutrients including lipids and iron transport. We found the Echinococcus specific Antigen B as well as several proteins involved in the energy metabolism
to be highly released into the in vitro culture medium and the vesicle fluid.
In summary, this thesis provides a solid basis for future confirmatory studies on novel candidate drugs and targets that will be useful for the development of novel treatments against infections with adult tapeworms and metacestodes of E. multilocularis.

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