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.
authors.affiliation: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom.|Drug Discovery Unit, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Patterson
authors.affiliation: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Susan
authors.identifier: 0000-0001-8810-5605
authors.initials: S
authors.lastname: Wyllie
authors.affiliation: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Norval
authors.affiliation: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom.|Drug Discovery Unit, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Laste
authors.initials: L
authors.lastname: Stojanovski
authors.affiliation: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom.|Drug Discovery Unit, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Frederick Rc
authors.initials: FR
authors.lastname: Simeons
authors.affiliation: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Auer
authors.affiliation: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom.|Drug Discovery Unit, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Osuna-Cabello
authors.affiliation: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom.|Drug Discovery Unit, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.affiliation: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom.|Drug Discovery Unit, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Alan H
authors.identifier: 0000-0001-5134-0329
authors.initials: AH
authors.lastname: Fairlamb
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000981:Antiprotozoal Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D058492:Drug Repositioning; D005260:Female; D059165:Hormesis; D007893:Leishmania donovani / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D007898:Leishmaniasis, Visceral / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009593:Nitroimidazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D010080:Oxazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D016896:Treatment Outcome
chemical_list: D000981:Antiprotozoal Agents; D000995:Antitubercular Agents; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles
keywords: Leishmania donovani; OPC-67683; Visceral leishmaniasis; drug repurposing; infectious disease; microbiology; mouse; pharmacodynamics; pharmacokinetics