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

Abstract

fThe 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 (IC 50 ). 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.

Chemotherapeutic Potential of Monensin as an Anti-microbial Agent

“…Surprisingly, monensin was able to completely inhibit P. vivax hypnozoites and schizonts suggesting its effectiveness in treating liver stage malaria [53]. Also, monensin could block the transmission of gametocytes at the sexual stage [54]. Malarial parasites treated with monensin led to accumulation of transport vesicles and blockade of vacuole-vesicle fusion suggesting that monensin targeted endocytic pathway [55].…”

In vitro inhibition of Plasmodium falciparum early and late stage gametocyte viability by extracts from eight traditionally used South African plant species

“…Dried crude acetone extracts were dissolved in DMSO as stock solutions and diluted in culture medium prior to their use in assays (highest concentration of DMSO to which parasites were exposed to was 0.4% (v/v) which is non-toxic to gametocytes (D'Alessandro et al, 2015(D'Alessandro et al, , 2013Duffy and Avery, 2013;Lucantoni et al, 2013). These extracts were transferred into 96 well sterile plates and seeded with an equal volume (100 µl/well) of gametocyte suspension (0.8-3% gametocytaemia) to achieve a final haematocrit of 1% et al, 2013).…”

“…Plates were incubated at 37ºC for 72 hours, followed by the replacement of spent medium with extract-free culture medium (75% medium change) (D'Alessandro et al, 2015(D'Alessandro et al, , 2013.…”

Stearylamine Liposomal Delivery of Monensin in Combination with Free Artemisinin Eliminates Blood Stages of Plasmodium falciparum in Culture and P. berghei Infection in Murine Malaria

“…Monensin, a polyether antibiotic ionophore, has been shown to exhibit antimalarial activity against P. falciparum in vitro (11,12) and Plasmodium vinckei petteri and Plasmodium chabaudi in vivo (12,13). This ionophore carries Na ϩ across intracellular organelle membranes and facilitates the exchange of H ϩ .…”