Salinomycin and Other Ionophores as a New Class of Antimalarial Drugs with Transmission-Blocking Activity

The drug target profile proposed by Medicine for Malaria Venture for the malaria elimination/eradication policy focuses on molecules active on both asexual and sexual stages of Plasmodium, thus with both curative and transmission blocking activity. The aim of the present work was to investigate whether the class of monovalent ionophores, which includes drugs used in veterinary medicine and recently proposed as human anticancer agents, meets these requirements. Here, the activity of salinomycin, monensin and nigericin on Plasmodium falciparum ( Pf ) asexual and sexual erythrocytic stages and on the development of the P. berghei ( Pb ) and Pf mosquito stages is reported. Gametocytogenesis of the 3D7 Pf strain was induced in vitro , gametocytes at stage II-III or stage IV-V of development were treated for different lengths of time with the ionophores and their viability measured with the pLDH assay. The monovalent ionophores efficiently killed both asexual parasites and gametocytes with nanomolar IC 50 . Salinomycin showed a fast speed of kill compared to standard drugs and the potency was higher on stage IV-V than on stage II and III gametocytes. The ionophores inhibited ookinete development and subsequent oocyst formation in the mosquito midgut, confirming a 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 downstream exploration of monovalent ionophores for repositioning as new antimalarial and transmission blocking leads.