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

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.

Parasites of the liver – epidemiology, diagnosis and clinical management in the European context

“…mefloquine), as well as new formulations of BMZ, are under investigation. 89 Currently, amphotericin B can be administered as an experimental approach. 90 Nitazoxanide failed to show efficacy.…”

Introduction To Echinococcosis and A Review of Treatment Panels

“…Mefloquine is another drug with antiparasitic efficacy and is used in the treatment of malaria caused by Plasmodium species and has proven to have efficacy against metacestodes of E. multilocularis (Stadelmann et al 2011;Küster et al 2011;Küster et al 2015;Lundström-Stadelmann et al 2020).…”

Salvage Therapy for Alveolar Echinococcosis—A Case Series

“…In these cases, no approved second-line medical treatment exists, although the clinical situation often urgently demands further options. Several substances have been reported to show anti-echinococcal properties, which can broadly be separated into anti-infectives, including antimalarial drugs, antineoplastic drugs and plant-based natural compounds [ 9 , 10 , 11 , 12 ]. Among these substances are both new compounds as well as repurposed drugs.…”

“…Another repurposed drug investigated as salvage therapy is atovaquone, which showed in vivo activity in mice against EM, especially in combination with ABZ [ 21 ], and mefloquine, which also showed activity against murine AE but worked only when given intraperitoneally, not orally [ 22 , 23 ]. Furthermore, niclosamide showed good in vivo activity against EM metacestodes, but its use is currently limited by poor oral bioavailability [ 11 ]. Check-point inhibitors have also been discussed as possible immunotherapy for AE, as anti-programmed death-ligand 1 (PD-L1) treatment of infected mice leads to a reduction in parasite load [ 24 ].…”