The anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasis

Stephen Patterson, Susan Wyllie, Suzanne Norval, Laste Stojanovski, Frederick R. C. Simeons, Jennifer L. Auer, Maria Osuna-Cabello, Kevin D. Read, Alan H. Fairlamb (Lead / Corresponding author)

Research output: Contribution to journalArticle

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111 Downloads (Pure)

Abstract

There is an urgent requirement for safe, oral and cost-effective drugs for the treatment of visceral leishmaniasis (VL). We report that delamanid (OPC-67683), an approved drug for multi-drug resistant tuberculosis, is a potent inhibitor of Leishmania donovani both in vitro and in vivo. Twice-daily oral dosing of delamanid at 30 mg kg(-1) for 5 days resulted in sterile cures in a mouse model of VL. Treatment with lower doses revealed a U-shaped (hormetic) dose-response curve with greater parasite suppression at 1 mg kg(-1) than at 3 mg kg(-1) (5 or 10 day dosing). Dosing delamanid for 10 days confirmed the hormetic dose-response and improved the efficacy at all doses investigated. Mechanistic studies reveal that delamanid is rapidly metabolised by parasites via an enzyme, distinct from the nitroreductase that activates fexinidazole. Delamanid has the potential to be repurposed as a much-needed oral therapy for VL.

Original languageEnglish
Article numbere09744
Pages (from-to)1-21
Number of pages21
JournaleLife
Volume5
DOIs
Publication statusPublished - 24 May 2016

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Visceral Leishmaniasis
Hormesis
Pharmaceutical Preparations
Parasites
Nitroreductases
Leishmania donovani
Multidrug-Resistant Tuberculosis
Drug Costs
OPC-67683
Enzymes
Costs

Cite this

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title = "The anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasis",
abstract = "There is an urgent requirement for safe, oral and cost-effective drugs for the treatment of visceral leishmaniasis (VL). We report that delamanid (OPC-67683), an approved drug for multi-drug resistant tuberculosis, is a potent inhibitor of Leishmania donovani both in vitro and in vivo. Twice-daily oral dosing of delamanid at 30 mg kg(-1) for 5 days resulted in sterile cures in a mouse model of VL. Treatment with lower doses revealed a U-shaped (hormetic) dose-response curve with greater parasite suppression at 1 mg kg(-1) than at 3 mg kg(-1) (5 or 10 day dosing). Dosing delamanid for 10 days confirmed the hormetic dose-response and improved the efficacy at all doses investigated. Mechanistic studies reveal that delamanid is rapidly metabolised by parasites via an enzyme, distinct from the nitroreductase that activates fexinidazole. Delamanid has the potential to be repurposed as a much-needed oral therapy for VL.",
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The anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasis. / Patterson, Stephen; Wyllie, Susan; Norval, Suzanne; Stojanovski, Laste; Simeons, Frederick R. C.; Auer, Jennifer L.; Osuna-Cabello, Maria; Read, Kevin D.; Fairlamb, Alan H. (Lead / Corresponding author).

In: eLife, Vol. 5, e09744, 24.05.2016, p. 1-21.

Research output: Contribution to journalArticle

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AU - Auer, Jennifer L.

AU - Osuna-Cabello, Maria

AU - Read, Kevin D.

AU - Fairlamb, Alan H.

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AB - There is an urgent requirement for safe, oral and cost-effective drugs for the treatment of visceral leishmaniasis (VL). We report that delamanid (OPC-67683), an approved drug for multi-drug resistant tuberculosis, is a potent inhibitor of Leishmania donovani both in vitro and in vivo. Twice-daily oral dosing of delamanid at 30 mg kg(-1) for 5 days resulted in sterile cures in a mouse model of VL. Treatment with lower doses revealed a U-shaped (hormetic) dose-response curve with greater parasite suppression at 1 mg kg(-1) than at 3 mg kg(-1) (5 or 10 day dosing). Dosing delamanid for 10 days confirmed the hormetic dose-response and improved the efficacy at all doses investigated. Mechanistic studies reveal that delamanid is rapidly metabolised by parasites via an enzyme, distinct from the nitroreductase that activates fexinidazole. Delamanid has the potential to be repurposed as a much-needed oral therapy for VL.

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