Repurposing niclosamide ethanolamine for alveolar echinococcosis reveals a disconnect between in vitro efficacy and in vivo outcome in the intraperitoneal infection model
Abstract
Background: Echinococcosis is a zoonotic disease caused by cestodes of the genus Echinococcus. Alveolar echinococcosis (AE), caused by E. multilocularis, primarily affects the liver and shows infiltrative, tumor-like growth of the metacestode stage. If untreated, AE is lethal. AE remains a neglected disease with current treatments based on albendazole or mebendazole that are parasitostatic, and not curative, underscoring the need for more effective therapies. Niclosamide is a chlorinated salicylanilide derivative with proven activities against intestinal helminths but is inactive against tissue-dwelling helminths due to poor absorption and limited bioavailability. In this study, we repurposed niclosamide ethanolamine (NEN), a formulation with improved systemic exposure, for the treatment of E. multilocularis infection in vitro and in vivo. Methodology/principal findings: We assessed the in vitro efficacy of niclosamide and NEN against E. multilocularis metacestode vesicles (IC50 < 0.2 µM) and primary parasite cells (IC50 < 0.3 µM), with active concentrations largely corresponding to NEN levels reachable in the liver. Metabolic analysis suggested that NEN acts as a mitochondrial uncoupler. Electron microscopy showed that NEN-treatments induced profound structural damage in the metacestode vesicle tissue, but mitochondrial ultrastructure was not notably affected. Conclusions/significance: Although niclosamide and NEN demonstrated potent activity against E. multilocularis in vitro, this efficacy did not translate in the mouse model. The lack of in vivo activity could be attributed to several factors such as infection model, limited drug uptake by the parasite in the animal, or the rapid metabolization of the compound. Future studies should explore novel niclosamide derivatives and formulations to enhance efficacy against AE in vivo. Author summary: Alveolar echinococcosis (AE) is a severe disease caused by the larval stage of the fox tapeworm Echinococcus multilocularis. The parasite forms tumor-like lesions in the liver and can spread to other organs. The currently licensed drugs for the treatment of AE are not always effective, require long-term use, and can cause side effects that frequently require treatment interruption. Therefore, safer and more efficacious treatment options are urgently needed.
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BibTeX
@article{preza2026repurposing,
title = {{Repurposing niclosamide ethanolamine for alveolar echinococcosis reveals a disconnect between in vitro efficacy and in vivo outcome in the intraperitoneal infection model}},
author = {Matias Preza and Nicole Dietrich and Pascal Zumstein and Judith Steinmann and Lea Hiller and Trix Zumkehr and Tobias Kampfer and Marylene Chollet-Krugler and Laura Vetter and Andrew Hemphill and Sarah Dion and Britta Lundström-Stadelmann},
journal = {PLoS Neglected Tropical Diseases},
year = {2026},
month = aug,
doi = {10.1371/journal.pntd.0014016},
url = {https://hal.science/hal-05767897v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Repurposing niclosamide ethanolamine for alveolar echinococcosis reveals a disconnect between in vitro efficacy and in vivo outcome in the intraperitoneal infection model
AU - Matias Preza
AU - Nicole Dietrich
AU - Pascal Zumstein
AU - Judith Steinmann
AU - Lea Hiller
AU - Trix Zumkehr
AU - Tobias Kampfer
AU - Marylene Chollet-Krugler
AU - Laura Vetter
AU - Andrew Hemphill
AU - Sarah Dion
AU - Britta Lundström-Stadelmann
PY - 2026
DA - 2026/08/31
JO - PLoS Neglected Tropical Diseases
DO - 10.1371/journal.pntd.0014016
UR - https://hal.science/hal-05767897v1
AB - Background: Echinococcosis is a zoonotic disease caused by cestodes of the genus Echinococcus. Alveolar echinococcosis (AE), caused by E. multilocularis, primarily affects the liver and shows infiltrative, tumor-like growth of the metacestode stage. If untreated, AE is lethal. AE remains a neglected disease with current treatments based on albendazole or mebendazole that are parasitostatic, and not curative, underscoring the need for more effective therapies. Niclosamide is a chlorinated salicylanilide derivative with proven activities against intestinal helminths but is inactive against tissue-dwelling helminths due to poor absorption and limited bioavailability. In this study, we repurposed niclosamide ethanolamine (NEN), a formulation with improved systemic exposure, for the treatment of E. multilocularis infection in vitro and in vivo. Methodology/principal findings: We assessed the in vitro efficacy of niclosamide and NEN against E. multilocularis metacestode vesicles (IC50 < 0.2 µM) and primary parasite cells (IC50 < 0.3 µM), with active concentrations largely corresponding to NEN levels reachable in the liver. Metabolic analysis suggested that NEN acts as a mitochondrial uncoupler. Electron microscopy showed that NEN-treatments induced profound structural damage in the metacestode vesicle tissue, but mitochondrial ultrastructure was not notably affected. Conclusions/significance: Although niclosamide and NEN demonstrated potent activity against E. multilocularis in vitro, this efficacy did not translate in the mouse model. The lack of in vivo activity could be attributed to several factors such as infection model, limited drug uptake by the parasite in the animal, or the rapid metabolization of the compound. Future studies should explore novel niclosamide derivatives and formulations to enhance efficacy against AE in vivo. Author summary: Alveolar echinococcosis (AE) is a severe disease caused by the larval stage of the fox tapeworm Echinococcus multilocularis. The parasite forms tumor-like lesions in the liver and can spread to other organs. The currently licensed drugs for the treatment of AE are not always effective, require long-term use, and can cause side effects that frequently require treatment interruption. Therefore, safer and more efficacious treatment options are urgently needed.
SN - 1935-2727
SN - 1935-2735
ER -