Ionophore–Phospholipid Interactions in Langmuir Films in Relation to Ionophore Selectivity toward Plasmodium-Infected Erythrocytes

Gumila, Catherine; Miquel, Geneviève; Seta, P.; Ancelin, Marie-Laure; Delort, Anne-Marie; Jeminet, Georges; Vial, Henri

doi:10.1006/jcis.1999.6432

Cited by 11 publications

(9 citation statements)

References 29 publications

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“…Similar findings were reported by Gumila et al (55) using asexual parasites and were attributed to the modification of the membrane properties of infected RBCs and the different phospholipid and lipid composition of parasite membranes. All ionophores strongly interact with phospholipid monolayers and facilitate the incorporation and transport of ions in low-cholesterol-containing membranes typical of asexual P. falciparum parasites (55,56). Whether this may also apply to gametocyte-infected RBCs is not known yet.…”

Section: Discussionsupporting

confidence: 90%

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

D’Alessandro

Corbett

Ilboudo

et al. 2015

Antimicrob Agents Chemother

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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.

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Section: Discussionsupporting

confidence: 90%

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

D’Alessandro

Corbett

Ilboudo

et al. 2015

Antimicrob Agents Chemother

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“…This suggests that the inhibitory effect of various formulations of monensin toward infected RBCs is independent of hemolysis. The degree of specificity of monensin toward the antimalarial activity of infected erythrocytes has been studied using lipid membrane models (40). Our results indicate that the enhanced antimalarial efficacy of monensin in liposomal formulations is due to preferential internalization of liposomes by parasitized RBCs (Fig.…”

Section: Discussionmentioning

confidence: 73%

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

Rajendran

Rohra

Raza

et al. 2016

Antimicrob Agents Chemother

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The global emergence of drug resistance in malaria is impeding the therapeutic efficacy of existing antimalarial drugs. Therefore, there is a critical need to develop an efficient drug delivery system to circumvent drug resistance. The anticoccidial drug monensin, a carboxylic ionophore, has been shown to have antimalarial properties. Here, we developed a liposome-based drug delivery of monensin and evaluated its antimalarial activity in lipid formulations of soya phosphatidylcholine (SPC) cholesterol (

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“…19,20) Since both halofantrine and lumefantrine act as antimalarial agents by targeting the lifecycle of the parasites in the erythrocytes, it is particularly relevant to examine how these drugs influence the fluidity of erythrocyte membranes. Erythrocyte membranes contain phosphatidylcholine, phosphatidylethanolamine and cholesterol as the major lipid components on a weight basis.…”

Section: Discussionmentioning

confidence: 99%

“…There is also a higher proportion of unsaturated phospholipids in egg lecithin. Erythrocyte membranes are widely studied as models for drug-membrane interaction 11,12) because they are readily isolated and are simple compared to other cell types due to the absence of a nuclear and cytoplasmic membranes. In addition, since halofantrine and lumefantrine act primarily against the plasmodial life stages in the erythrocytes, it would be interesting to evaluate their effects on erythrocyte membranes from malarial infected mice.…”

mentioning

confidence: 99%

Interaction of the Antimalarial Agents Halofantrine and Lumefantrine with Lipid Bilayers

2003

CHEMICAL & PHARMACEUTICAL BULLETIN

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The effects of antimalarial drugs halofantrine and lumefantrine on the fluoresence anisotropy of diphenylhexatriene (DPH)-containing phospholipid vesicles have been examined. Lumefantrine increases DPH anisotropy, indicating a condensing effect on bilayers of dipalmitoylphosphatidyl choline (DPPC), dioleoylphosphatidylcholine (DOPC), egg lecithin and mouse erythrocyte membranes (including membranes isolated from plasmodial-infected mice). Its condensing effect is more pronounced in bilayers of lower microviscosity. In contrast, increases or decreases in DPH anisotropy are observed with halofantrine, depending on the nature of the lipid. Decreases in anisotropy, which reflect a perturbing effect, are observed in bilayers of high microviscosity (for example, gel state of DPPC bilayers). Increases in anisotropy are observed in bilayers of low microviscosity (such as DOPC and egg lecithin bilayers). The perturbing effect of halofantrine is further confirmed by the increases in permeability of calcein-containing DPPC vesicles in the presence of the drug. However the perturbative effects of halofantrine are observed to the same magnitude in uninfected and plasmodial-infected erythrocyte membranes, and may not be relevant to the antimalarial action of the drug. In contrast, the condensing effect of lumefantrine is significantly greater in infected erythrocyte membranes and may contribute to its antimalarial action.

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Ionophore–Phospholipid Interactions in Langmuir Films in Relation to Ionophore Selectivity toward Plasmodium-Infected Erythrocytes

Cited by 11 publications

References 29 publications

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

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

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

Interaction of the Antimalarial Agents Halofantrine and Lumefantrine with Lipid Bilayers

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