title: Salinomycin and other ionophores as a new class of antimalarial drugs with transmission-blocking activity.
abstract: The drug target profile proposed by the Medicines for Malaria Venture for a malaria elimination/eradication policy focuses on molecules active on both asexual and sexual stages of Plasmodium, thus with both curative and transmission-blocking activities. The aim of the present work was to investigate whether the class of monovalent ionophores, which includes drugs used in veterinary medicine and that were recently proposed as human anticancer agents, meets these requirements. The activity of salinomycin, monensin, and nigericin on Plasmodium falciparum asexual and sexual erythrocytic stages and on the development of the Plasmodium berghei and P. falciparum mosquito stages is reported here. Gametocytogenesis of the P. falciparum strain 3D7 was induced in vitro, and gametocytes at stage II and III or stage IV and V of development were treated for different lengths of time with the ionophores and their viability measured with the parasite lactate dehydrogenase (pLDH) assay. The monovalent ionophores efficiently killed both asexual parasites and gametocytes with a nanomolar 50% inhibitory concentration (IC50). Salinomycin showed a fast speed of kill compared to that of standard drugs, and the potency was higher on stage IV and V than on stage II and III gametocytes. The ionophores inhibited ookinete development and subsequent oocyst formation in the mosquito midgut, confirming their transmission-blocking activity. Potential toxicity due to hemolysis was excluded, since only infected and not normal erythrocytes were damaged by ionophores. Our data strongly support the downstream exploration of monovalent ionophores for repositioning as new antimalarial and transmission-blocking leads.
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: D'Alessandro
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Corbett
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
authors.forename: Denise P
authors.initials: DP
authors.lastname: Ilboudo
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Misiano
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Camerino, Macerata, Italy.
authors.forename: Nisha
authors.initials: N
authors.lastname: Dahiya
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Camerino, Macerata, Italy.
authors.forename: Solomon M
authors.initials: SM
authors.lastname: Abay
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Camerino, Macerata, Italy.
authors.forename: Annette
authors.initials: A
authors.lastname: Habluetzel
authors.affiliation: L. Sacco University Hospital, Milan, Italy.
authors.forename: Romualdo
authors.initials: R
authors.lastname: Grande
authors.affiliation: L. Sacco University Hospital, Milan, Italy.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Gismondo
authors.affiliation: TropIQ Health Sciences, Nijmegen, The Netherlands.
authors.forename: Koen J
authors.initials: KJ
authors.lastname: Dechering
authors.affiliation: TropIQ Health Sciences, Nijmegen, The Netherlands.
authors.forename: Karin M J
authors.initials: KM
authors.lastname: Koolen
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sauerwein
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Taramelli
authors.affiliation: Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università degli Studi di Milano, Milan, Italy nicoletta.basilico@unimi.it.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Basilico
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Parapini
mesh_terms: D000962:Antimalarials / Q000009:adverse effects / Q000494:pharmacology*; D002460:Cell Line; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007476:Ionophores / Q000009:adverse effects / Q000494:pharmacology*; D015394:Molecular Structure; D008985:Monensin / Q000009:adverse effects / Q000494:pharmacology; D009550:Nigericin / Q000009:adverse effects / Q000494:pharmacology; D010962:Plasmodium berghei / Q000187:drug effects / Q000472:pathogenicity; D010963:Plasmodium falciparum / Q000187:drug effects / Q000472:pathogenicity; D011714:Pyrans / Q000009:adverse effects / Q000494:pharmacology*; D000095662:Polyether Polyketides
chemical_list: D000962:Antimalarials; D007476:Ionophores; D008985:Monensin; D009550:Nigericin; D011714:Pyrans; C010327:salinomycin; D000095662:Polyether Polyketides