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 | |
| Publication status | Published - 24 May 2016 |
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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
TY - JOUR
T1 - The anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasis
AU - Patterson, Stephen
AU - Wyllie, Susan
AU - Norval, Suzanne
AU - Stojanovski, Laste
AU - Simeons, Frederick R. C.
AU - Auer, Jennifer L.
AU - Osuna-Cabello, Maria
AU - Read, Kevin D.
AU - Fairlamb, Alan H.
PY - 2016/5/24
Y1 - 2016/5/24
N2 - 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.
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.
U2 - 10.7554/eLife.09744
DO - 10.7554/eLife.09744
M3 - Article
C2 - 27215734
VL - 5
SP - 1
EP - 21
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e09744
ER -