Título:
In vitro screening of the open-access Pandemic Response Box reveals ESI-09 as a compound with activity against Echinococcus multilocularis
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Autor:
Zumstein, Pascal
Bartetzko, Anissa
Kaethner, Marc
Vetter, Laura
Hemphill, Andrew
Zumkehr, Trix
Laleu, Benoît
Preza Pérez, Matías Facundo
Lundström-Stadelmann, Britta
Bartetzko, Anissa
Kaethner, Marc
Vetter, Laura
Hemphill, Andrew
Zumkehr, Trix
Laleu, Benoît
Preza Pérez, Matías Facundo
Lundström-Stadelmann, Britta
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Tipo de documento:
Artículo
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Palabras clave:
Echinococcus mutlilocularis
Alveolar echinococcosis
Drug repurposing
MMV
DNDi
Mitochondrial uncoupler
Alveolar echinococcosis
Drug repurposing
MMV
DNDi
Mitochondrial uncoupler
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Año de publicación:
2025
Contenido:
Resumen:
Alveolar echinococcosis (AE) is a life-threatening disease caused by the metacestode stage of the fox tapeworm
Echinococcus multilocularis, primarily in the liver. Current drug treatments rely on benzimidazoles, which are not
parasiticidal, requiring life-long therapy with significant side effects. Therefore, novel drug treatments are urgently needed. Drug repurposing offers a strategy to identify novel therapies against the neglected disease AE. We report on the in vitro screening of the Pandemic Response Box, an open-access compound library composed of 400 drug-like molecules assembled by Medicines for Malaria Venture (MMV) and the Drugs for Neglected Disease Initiative (DNDi), against E. multilocularis. An overview screen at 10 μM using the metacestode vesicle damage-marker release assay (based on release of phosphoglucose isomerase, PGI) and metacestode vesicle viability assay
(based on ATP measurement) identified 37 active compounds. Reassessment in triplicates resulted in five active
compounds (alexidine, carbendazim, ESI-09, MMV1581545, oxfendazole) displaying anti-metacestode activity.
The parasiticidal activity of these five compounds was evaluated by ATP measurement in germinal layer cells.
One compound, ESI-09, acted specifically against E. multilocularis (IC50 on metacestode vesicles 6.06 ± 3.18 μM
by PGI release assay and 2.09 ± 0.56 μM by metacestode vesicle viability assay as well as an IC50 of 2.45 ± 0.86
μM on germinal layer cells) with a broad therapeutic window when compared to mammalian cell toxicity.
Further experiments applying Seahorse technology and tetramethylrhodamine ethyl ester (TMRE) assay revealed
that ESI-09 acts as a mitochondrial uncoupler in parasite cells. However, transmission electron microscopy
showed no significant ultrastructural changes in parasite mitochondria, though increased secretion of extracel-
lular vesicle-like structures between the tegument and the laminated layer was observed. In summary, screening
of the Pandemic Response Box identified ESI-09 as a potential drug candidate for the treatment of AE. Further
experiments are needed to evaluate the efficacy of ESI-09 in vivo.
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Elsevier
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International Journal for Parasitology: Drugs and Drug Resistance, 2025, 29: 100609.
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Citación:
Zumstein, P, Bartetzko, A, Kaethner, M [y otros autores]. "In vitro screening of the open-access Pandemic Response Box reveals ESI-09 as a compound with activity against Echinococcus multilocularis". International Journal for Parasitology: Drugs and Drug Resistance. [en línea] 2025, 29: 100609. 11 h. DOI: 10.1016/j.ijpddr.2025.100609
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2211-3207
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Licencia Creative Commons Atribución (CC - By 4.0)
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| Ficheros | Descripción | Tamaño | Formato | ||
|---|---|---|---|---|---|
| 10.101.j.ijpddr.2025.100609.pdf | — | 6.95 MB | Adobe PDF |