Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis

• DOI: 10.1016/j.ijpddr.2020.06.002
• Publication Date: 2020-07-02T15:40:54Z
• Authors: Britta Lundström-...; Reto Rufener; Andrew Hemphill
• Keywords: 615 Pharmacology & therapeutics, prescription drugs; 0301 basic medicine; Drug Evaluation, Preclinical; 610 Medicine & health; Infectious and parasitic diseases; RC109-216; Albendazole; Article; Antimalarials; Mice; 03 medical and health sciences; Echinococcosis; Animals; Humans; Atovaquone; 630 Agriculture; Metacestode; Alveolar echinococcosis; MMV665807; Drug Repositioning; Anticestodal Agents; Energy-metabolism; 500 Science; 3. Good health; Mefloquine; Disease Models, Animal; Ferritins; 570 Life sciences; biology; Niclosamide; Echinococcus multilocularis

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.