Mitochondrial complex III in larval stage of Echinococcus multilocularis as a potential chemotherapeutic target and in vivo efficacy of atovaquone against primary hydatid cysts

Enkai, Shigehiro; Inaoka, Daniel Ken; Kouguchi, Hirokazu; Irie, Takao; Yagi, Kinpei; Kita, Kiyoshi

doi:10.1016/j.parint.2019.102004

Cited by 23 publications

(37 citation statements)

References 45 publications

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“…Recently, two studies reported on the successful inhibition of the electron transfer chain in E. multilocularis GL cells and metacestodes by atovaquone, buparvaquone, and the endochin-like quinolone ELQ-400 ( Rufener et al, 2018a ; Enkai et al, 2020 ). Thus, the respective target, the complex III of the mitochondrial respiration chain, could be further followed up with more selective inhibitors.…”

Section: Identification Of Novel Drugs Against Alveolar Echinococcosimentioning

confidence: 99%

“…A plethora of anti-infective compounds were tested against E. multilocularis in rodent models and in vitro in the past ( Lundström-Stadelmann et al, 2019 ), including (i) BMZ ( Siles-Lucas et al, 2018 ), (ii) nitazoxanide ( Stettler et al, 2003 ), (iii) amphotericin B and itraconazole ( Reuter et al, 2003 , 2006 ), (iv) inhibitors of the mitochondrial respiration chain ( Enkai et al, 2020 ; Rufener et al, 2018a ), and (v) mefloquine (further discussed in chapter 4 and following).…”

Section: Identification Of Novel Drugs Against Alveolar Echinococcosimentioning

confidence: 99%

“…(iv) Inhibitors of the mitochondrial respiratory chain (i.e. buparvaquone, atovaquone and the endochin-like quinolone ELQ-400) were identified as highly active compounds in vitro ( Rufener et al, 2018a ; Enkai et al, 2020 ). Atovaquone exhibited activity in the primary mouse infection model against AE ( Enkai et al, 2020 ), whereas buparvaquone was not active in the secondary AE mouse infection model, presumably due to the fast metabolization and short plasma half-life of buparvaquone ( Rufener et al, 2018a ).…”

Section: Identification Of Novel Drugs Against Alveolar Echinococcosimentioning

confidence: 99%

“…buparvaquone, atovaquone and the endochin-like quinolone ELQ-400) were identified as highly active compounds in vitro ( Rufener et al, 2018a ; Enkai et al, 2020 ). Atovaquone exhibited activity in the primary mouse infection model against AE ( Enkai et al, 2020 ), whereas buparvaquone was not active in the secondary AE mouse infection model, presumably due to the fast metabolization and short plasma half-life of buparvaquone ( Rufener et al, 2018a ). Further analyses revealed that buparvaquone, atovaquone, and most likely also ELQ-400, inhibit the mitochondrial complex III in E. multilocularis ( Rufener et al, 2018a ; Enkai et al, 2020 ).…”

Section: Identification Of Novel Drugs Against Alveolar Echinococcosimentioning

confidence: 99%

“…Atovaquone exhibited activity in the primary mouse infection model against AE ( Enkai et al, 2020 ), whereas buparvaquone was not active in the secondary AE mouse infection model, presumably due to the fast metabolization and short plasma half-life of buparvaquone ( Rufener et al, 2018a ). Further analyses revealed that buparvaquone, atovaquone, and most likely also ELQ-400, inhibit the mitochondrial complex III in E. multilocularis ( Rufener et al, 2018a ; Enkai et al, 2020 ). These inhibitors of the respiratory chain will have to be investigated further to determine whether they can be translated into a promising treatment option against human AE.…”

Section: Identification Of Novel Drugs Against Alveolar Echinococcosimentioning

confidence: 99%

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

Lundström‐Stadelmann

Rufener

Hemphill

2020

International Journal for Parasitology: Drugs and Drug Resistan

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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.

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Section: Identification Of Novel Drugs Against Alveolar Echinococcosimentioning

confidence: 99%

Section: Identification Of Novel Drugs Against Alveolar Echinococcosimentioning

confidence: 99%

Section: Identification Of Novel Drugs Against Alveolar Echinococcosimentioning

confidence: 99%

Section: Identification Of Novel Drugs Against Alveolar Echinococcosimentioning

confidence: 99%

Section: Identification Of Novel Drugs Against Alveolar Echinococcosimentioning

confidence: 99%

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

Lundström‐Stadelmann

Rufener

Hemphill

2020

International Journal for Parasitology: Drugs and Drug Resistan

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Current Treatments for Echinococcosis What We Have

Fan

2024

Parasitology Research Monographs

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Novel Chemotherapeutical Approaches Against Echinococcosis: A Swiss Perspective

Lundström-Stadelmann,

Preza,

Kaethner

et al. 2024

Parasitology Research Monographs

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Mitochondrial complex III in larval stage of Echinococcus multilocularis as a potential chemotherapeutic target and in vivo efficacy of atovaquone against primary hydatid cysts

Cited by 23 publications

References 45 publications

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

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

Current Treatments for Echinococcosis What We Have

Novel Chemotherapeutical Approaches Against Echinococcosis: A Swiss Perspective

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