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Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis.
Int J Parasitol Drugs Drug Resist. 2020 Aug; 13:121-129.IJ

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.

Authors+Show Affiliations

Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Längggassstrasse 122, 3012, Bern, Switzerland. Electronic address: britta.lundstroem@vetsuisse.unibe.ch.Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Längggassstrasse 122, 3012, Bern, Switzerland.Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Längggassstrasse 122, 3012, Bern, Switzerland.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32636148

Citation

Lundström-Stadelmann, Britta, et al. "Drug Repurposing Applied: Activity of the Anti-malarial Mefloquine Against Echinococcus Multilocularis." International Journal for Parasitology. Drugs and Drug Resistance, vol. 13, 2020, pp. 121-129.
Lundström-Stadelmann B, Rufener R, Hemphill A. Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis. Int J Parasitol Drugs Drug Resist. 2020;13:121-129.
Lundström-Stadelmann, B., Rufener, R., & Hemphill, A. (2020). Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis. International Journal for Parasitology. Drugs and Drug Resistance, 13, 121-129. https://doi.org/10.1016/j.ijpddr.2020.06.002
Lundström-Stadelmann B, Rufener R, Hemphill A. Drug Repurposing Applied: Activity of the Anti-malarial Mefloquine Against Echinococcus Multilocularis. Int J Parasitol Drugs Drug Resist. 2020;13:121-129. PubMed PMID: 32636148.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis. AU - Lundström-Stadelmann,Britta, AU - Rufener,Reto, AU - Hemphill,Andrew, Y1 - 2020/07/02/ PY - 2020/05/02/received PY - 2020/05/29/revised PY - 2020/06/03/accepted PY - 2020/7/9/pubmed PY - 2020/7/9/medline PY - 2020/7/9/entrez KW - Alveolar echinococcosis KW - Atovaquone KW - Energy-metabolism KW - MMV665807 KW - Metacestode KW - Niclosamide SP - 121 EP - 129 JF - International journal for parasitology. Drugs and drug resistance JO - Int J Parasitol Drugs Drug Resist VL - 13 N2 - 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. SN - 2211-3207 UR - https://www.unboundmedicine.com/medline/citation/32636148/Drug_repurposing_applied:_Activity_of_the_anti-malarial_mefloquine_against_Echinococcus_multilocularis L2 - https://linkinghub.elsevier.com/retrieve/pii/S2211-3207(20)30015-4 DB - PRIME DP - Unbound Medicine ER -
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