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.
Highlights
The repurposing of drugs and clinical candidates offers an attractive alternative to de novo drug discovery (Fischbach and Walsh, 2009; Cragg et al, 2014; Peters, 2013; Law et al, 2013; Novac, 2013; Aube, 2012), in terms of reducing research and development costs for neglected diseases of poverty (Andrews et al, 2014)
Visceral leishmaniasis (VL), a neglected tropical disease resulting from infection with the protozoan parasites Leishmania donovani or L. infantum is a case in point, with the two anti-leishmanial front-line therapies miltefosine and amphotericin B both originally developed for other indications (Stuart et al, 2008)
The life cycle of L. donovani alternates between a flagellated promastigote form residing in the alkaline midgut of the female sandfly vector and an amastigote form that multiplies intracellularly in acidic phagolysosomes of the mammalian host macrophages
Summary
The repurposing of drugs and clinical candidates offers an attractive alternative to de novo drug discovery (Fischbach and Walsh, 2009; Cragg et al, 2014; Peters, 2013; Law et al, 2013; Novac, 2013; Aube, 2012), in terms of reducing research and development costs for neglected diseases of poverty (Andrews et al, 2014). Visceral leishmaniasis (VL), a neglected tropical disease resulting from infection with the protozoan parasites Leishmania donovani or L. infantum is a case in point, with the two anti-leishmanial front-line therapies miltefosine and amphotericin B both originally developed for other indications (Stuart et al, 2008). Each of the currently available drugs has one or more drawbacks, including the need for hospitalization, prolonged therapy, parenteral administration, high cost, variable efficacy, severe toxic side-effects and resistance (Croft et al, 2006). There is an urgent need for better, safer efficacious drugs that are fit-for-purpose in resource-poor settings
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