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.

当前针对肺泡棘球菌病的化学治疗方法仅依赖于苯并咪唑类药物，苯并咪唑类药物不是杀寄生虫的，并且可以引起严重的毒性。没有其他治疗选择。为了鉴定对多棘棘球E球菌有活性的新药，研究人员研究了潜在有趣的药物靶标（例如，寄生虫的能量代谢），和/或通过进行全生物体筛选采用了药物重用方法。我们在这里专注于药物筛选方法，该方法利用了体外筛选级联反应，包括评估药物引起的后代器官的物理损伤，对后代细胞活力和离体寄生虫干细胞活力的影响，化合物衍生物的结构活性关系（SAR）分析以及作用方式。最后，一旦体外数据指示治疗窗口，就可以在实验感染的小鼠中评估所选化合物的功效。使用这种筛选级联，我们发现抗疟药的甲氟喹在体外和体内对多叶大肠杆菌的代谢都具有活性。为了使更多信息了解甲氟喹的作用方式，对甲氟喹类似物进行了SAR分析。多叶大肠杆菌铁蛋白被确定为甲氟喹结合蛋白，但其作为药物靶标的确切作用尚待阐明。与标准阿苯达唑治疗相比，在小鼠腹腔内被子囊内感染或口服卵感染的小鼠中，甲氟喹口服治疗导致寄生虫生长显着减少。然而，甲氟喹没有寄生作用。对治疗的小鼠中甲氟喹血浆浓度的评估表明，达到的水平接近于长期预防疟疾期间人类所达到的血清浓度。甲氟喹可以作为挽救疗法用于人类AE患者。未来的研究应侧重于其他用途更广泛的抗感染化合物（MMV665807，尼克洛沙胺，阿托伐醌），它们在体外具有更强的抗感染性对多叶大肠杆菌的活性要高于甲氟喹。