New drugs against Echinococcus multilocularis targeting the energy metabolism

Rufener, Reto (2020). New drugs against Echinococcus multilocularis targeting the energy metabolism (Unpublished). (Dissertation, Institut für Parasitologie IPA, Vetsuisse)

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The larval stage (metacestode) of the fox tapeworm (Echinococcus multilocularis) causes alveolar echinococcosis (AE), which is a life-threatening, zoonotic disease of the Northern hemisphere. Current treatment options consist of surgical and chemotherapeutic interventions. However, they have several drawbacks and are not always feasible; hence there is a need of new, improved chemotherapeutic treatment options against AE. To do so, we developed and refined in vitro assays to test hundreds of molecules for their activity against E. multilocularis, eventually followed by in vivo studies. By applying these assays in a screening cascade, we screened the Malaria Box and the Pathogen Box from Medicines for Malaria Venture. We identified several compounds with distinct activities against the parasite, most notably mefloquine, MMV665807, niclosamide, buparvaquone, and ELQ-400. As for mefloquine, we assessed its pharmacokinetic properties in mice with AE after continuous treatment, concluding that mefloquine could potentially be exploited to treat AE in humans. By investigating the mechanism of action of the other active compounds, we discovered that
they interfere with the mitochondrial energy metabolism, either by inhibiting the cytochrome bc1 complex or by acting as mitochondrial uncouplers. Furthermore, we examined the host-parasite interface of in vitro cultivated parasites by investigating the metabolic footprint with 1H nuclear magnetic resonance spectroscopy. From these data we discovered that the amino acid threonine (potentially serving as an energy source for the metacestode), as well as the malate dismutation pathway (to degrade carbohydrates anaerobically to generate energy) play a crucial role for E. multilocularis.
Altogether, we concluded that targeting the energy metabolism of E. multilocularis is a potentially beneficial strategy to discover new and improved treatment options against AE.

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