Abstract
The current chemotherapeutical treatment against alveolar echinococcosis relies exclusively on benzimidazoles, which are not parasiticidal and can induce severe toxicity. There are no alternative treatment options. To identify novel drugs with activity against Echinococcus multilocularis metacestodes, researchers have studied potentially interesting drug targets (e.g. the parasite's energy metabolism), and/or adopted drug repurposing approaches by undertaking whole organism screenings. We here focus on drug screening approaches, which utilize an in vitro screening cascade that includes assessment of the drug-induced physical damage of metacestodes, the impact on metacestode viability and the viability of isolated parasite stem cells, structure-activity relationship (SAR) analysis of compound derivatives, and the mode of action. Finally, once in vitro data are indicative for a therapeutic window, the efficacy of selected compounds is assessed in experimentally infected mice. Using this screening cascade, we found that the anti-malarial mefloquine was active against E. multilocularis metacestodes in vitro and in vivo. To shed more light into the mode of action of mefloquine, SAR analysis on mefloquine analogues was performed. E. multilocularis ferritin was identified as a mefloquine-binding protein, but its precise role as a drug target remains to be elucidated. In mice that were infected either intraperitoneally with metacestodes or orally with eggs, oral treatment with mefloquine led to a significant reduction of parasite growth compared to the standard treatment with albendazole. However, mefloquine was not acting parasiticidally. Assessment of mefloquine plasma concentrations in treated mice showed that levels were reached which are close to serum concentrations that are achieved in humans during long-term malaria prophylaxis. Mefloquine might be applied in human AE patients as a salvage treatment. Future studies should focus on other repurposed anti-infective compounds (MMV665807, niclosamide, atovaquone), which showed stronger in vitro activity against E. multilocularis than mefloquine.
Highlights
The current chemotherapeutical treatment against alveolar echinococcosis relies exclusively on benzimidazoles, which are not parasiticidal and can induce severe toxicity
Trifluoromethyl residue on position 8 of the quinoline structure (Rufener et al, 2018b). This is in line with the anti-malarial activity of mefloquine and it implies that the mode of action in E. multilocularis might be similar to the one against Plasmodium
Apart from mefloquine, several anti-malarials have been shown to be efficacious against parasitic helminths (Panic et al, 2014), and some of them were tested for their efficacy against E. multilocularis metacestodes: artesunate and semi-synthetic derivatives were active in vitro, but not in the murine Alveolar echinococcosis (AE) model (Spicher et al, 2008b), synthetic amino-ozonides were partially active against metacestodes in vitro (Küster et al, 2014a), and atovaquone was efficacious in vitro and in experimentally infected mice (Enkai et al, 2020)
Summary
Alveolar echinococcosis (AE) is caused by the cestode Echinococcus multilocularis (small fox tapeworm). To conclude the parasite life cycle, ingestion of a naturally infected rodent by a final host results in attachment of protoscoleces to the intestinal wall of the final host, followed by the development of adult tapeworms (Romig et al, 2017). It has been hypothesized that, at least in Switzerland, only a small fraction of people exposed to infectious E. multilocularis eggs develop a progressive form of the disease (Gottstein et al, 2015b). The reasons for this are still unknown, but the immune system is crucial in determining the final outcome of infection. Several studies reported on the rapid development of AE in HIV patients (Sailer et al, 1997; Zingg et al, 2004), and others have brought up the increased risk of occurrence and progression of AE in immunosuppressed patients (Chauchet et al, 2014; Gottstein et al, 2015b; Lachenmayer et al, 2019)
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