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

doi:10.7554/eLife.09744

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 journal › Article › peer-review

44 Citations (Scopus)

220 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 language	English
Article number	e09744
Pages (from-to)	1-21
Number of pages	21
Journal	eLife
Volume	5
DOIs	https://doi.org/10.7554/eLife.09744
Publication status	Published - 24 May 2016

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10.7554/eLife.09744Licence: CC BY

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2 Finished

Discovery and Development of Drug Candidates for Neglected Diseases (joint with industrial partner)
Brenk, R., Fairlamb, A., Ferguson, M., Field, M., Gilbert, I., Gray, D., Hopkins, A., Horn, D., Read, K., Wyatt, P. & van Aalten, D.
Wellcome Trust
1/02/11 → 1/07/17
Project: Research
Aref#d: 18185. Characterization and validation of drug targets in the Kinetoplastida (Principal Research Fellowship/Programme Grant)
Fairlamb, A.
Wellcome Trust
1/10/06 → 30/09/17
Project: Research

The metabolism of bicyclic nitro drugs in Leishmania
Author: Norval, S., 2016
Supervisor: Read, K. (Supervisor) & Fairlamb, A. (Supervisor)
Student thesis: Doctoral Thesis › Doctor of Philosophy

Fairlamb, Alan
- Biological Chemistry and Drug Discovery - Consulting Professor & Consulting Professor of Biochemistry
Person: Academic

Cite this

@article{b02860b9ff764c86894e2371824f0341,

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.",

author = "Stephen Patterson and Susan Wyllie and Suzanne Norval and Laste Stojanovski and Simeons, {Frederick R. C.} and Auer, {Jennifer L.} and Maria Osuna-Cabello and Read, {Kevin D.} and Fairlamb, {Alan H.}",

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doi = "10.7554/eLife.09744",

language = "English",

volume = "5",

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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 journal › Article › peer-review

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AU - Simeons, Frederick R. C.

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

Abstract

Access to Document

Discovery and Development of Drug Candidates for Neglected Diseases (joint with industrial partner)

Aref#d: 18185. Characterization and validation of drug targets in the Kinetoplastida (Principal Research Fellowship/Programme Grant)

The metabolism of bicyclic nitro drugs in Leishmania

Fairlamb, Alan

Cite this