Repurposing of an old drug: In vitro and in vivo efficacies of buparvaquone against Echinococcus multilocularis

Rufener, Reto; Dick, Luca; D'Ascoli, Laura; Ritler, Dominic; Hizem, Amani; Wells, Timothy N.C.; Hemphill, Andrew; Lundström-Stadelmann, Britta (2018). Repurposing of an old drug: In vitro and in vivo efficacies of buparvaquone against Echinococcus multilocularis. International journal for parasitology. Drugs and drug resistance, 8(3), pp. 440-450. Elsevier 10.1016/j.ijpddr.2018.10.011

[img]
Preview
Text
1-s2.0-S2211320718301222-main.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (1MB) | Preview

The metacestode stage of the fox tapeworm Echinococcus multilocularis causes the lethal disease alveolar echinococcosis. Current chemotherapeutic treatment options are based on benzimidazoles (albendazole and mebendazole), which are insufficient and hence alternative drugs are needed. In this study, we screened the 400 compounds of the Medicines for Malaria Venture (MMV) Pathogen Box against E. multilocularis metacestodes. For the screen, we employed the phosphoglucose isomerase (PGI) assay which assesses drug-induced damage on metacestodes, and identified ten new compounds with activity against the parasite. The anti-theilerial drug MMV689480 (buparvaquone) and MMV671636 (ELQ-400) were the most promising compounds, with an IC50 of 2.87 μM and 0.02 μM respectively against in vitro cultured E. multilocularis metacestodes. Both drugs suggested a therapeutic window based on their cytotoxicity against mammalian cells. Transmission electron microscopy revealed that treatment with buparvaquone impaired parasite mitochondria early on and additional tests showed that buparvaquone had a reduced activity under anaerobic conditions. Furthermore, we established a system to assess mitochondrial respiration in isolated E. multilocularis cells in real time using the Seahorse XFp Analyzer and demonstrated inhibition of the cytochrome bc1 complex by buparvaquone. Mice with secondary alveolar echinococcosis were treated with buparvaquone (100 mg/kg per dose, three doses per week, four weeks of treatment), but the drug failed to reduce the parasite burden in vivo. Future studies will reveal whether improved formulations of buparvaquone could increase its effectivity.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Parasitology
05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction

UniBE Contributor:

Rufener, Reto; Dick, Luca Julian; Ritler, Dominic; Hemphill, Andrew and Lundström Stadelmann, Britta

Subjects:

600 Technology > 630 Agriculture

ISSN:

2211-3207

Publisher:

Elsevier

Language:

English

Submitter:

Britta Lundström Stadelmann

Date Deposited:

07 Nov 2018 12:15

Last Modified:

17 Dec 2018 08:50

Publisher DOI:

10.1016/j.ijpddr.2018.10.011

PubMed ID:

30396011

BORIS DOI:

10.7892/boris.120963

URI:

https://boris.unibe.ch/id/eprint/120963

Actions (login required)

Edit item Edit item
Provide Feedback