Abstract
The metacestode stage of the fox tapeworm Echinococcus multilocularis causes the lethal disease alveolar echinococcosis. Current chemotherapeutic treatment options are based on benzimidazoles (albendazole and mebendazole), which are insufficient and hence alternative drugs are needed. In this study, we screened the 400 compounds of the Medicines for Malaria Venture (MMV) Pathogen Box against E. multilocularis metacestodes. For the screen, we employed the phosphoglucose isomerase (PGI) assay which assesses drug-induced damage on metacestodes, and identified ten new compounds with activity against the parasite. The anti-theilerial drug MMV689480 (buparvaquone) and MMV671636 (ELQ-400) were the most promising compounds, with an IC50 of 2.87 μM and 0.02 μM respectively against in vitro cultured E. multilocularis metacestodes. Both drugs suggested a therapeutic window based on their cytotoxicity against mammalian cells. Transmission electron microscopy revealed that treatment with buparvaquone impaired parasite mitochondria early on and additional tests showed that buparvaquone had a reduced activity under anaerobic conditions. Furthermore, we established a system to assess mitochondrial respiration in isolated E. multilocularis cells in real time using the Seahorse XFp Analyzer and demonstrated inhibition of the cytochrome bc1 complex by buparvaquone. Mice with secondary alveolar echinococcosis were treated with buparvaquone (100 mg/kg per dose, three doses per week, four weeks of treatment), but the drug failed to reduce the parasite burden in vivo. Future studies will reveal whether improved formulations of buparvaquone could increase its effectivity.
Highlights
Alveolar Echinococcosis (AE) is a life-threatening disease caused by infections with the fox tapeworm Echinococcus multilocularis which is endemic in the Northern hemisphere
Four were reference compounds of the Pathogen Box (MMV000016, mefloquine; MMV688978, auranofin; MMV688991, nitazoxanide, and MMV689480, BPQ), four compounds were from the tuberculosis disease set (MMV021013, MMV090930, MMV687730, and MMV687807), two compounds were from the malaria disease set (MMV011903 and MMV026468), and one compound each was from the onchocerciasis, cryptosporidiosis, and kinetoplastid disease set (MMV671636, MMV675994, and MMV690102)
The EC50 are representative for the activity in the metacestode phosphoglucose isomerase (PGI)-assay, and the minimal inhibitory concentrations (MICs) for the parasiticidal potential in the vesicle viability assay by Alamar Blue assay
Summary
Alveolar Echinococcosis (AE) is a life-threatening disease caused by infections with the fox tapeworm Echinococcus multilocularis which is endemic in the Northern hemisphere. Complete surgical removal of the parasitic lesions is often not possible, due to the diffuse and infiltrative nature of the metacestode tissue (Grüner et al, 2017; Kern et al, 2017). In such cases, chemotherapy remains the only widely used treatment option against AE. The current drugs of choice are the benzimidazole derivatives albendazole (ABZ) and mebendazole They have several drawbacks, most importantly they act parasitostatic rather than parasiticidal (Hemphill et al, 2014, 2007), they have only limited potential to bring about a cure from infection, and massive doses of these drugs usually have to be administered throughout life (Kern et al, 2017). All these shortcomings make it urgent to develop alternative chemotherapeutic options against
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