Inhibition of Plasmodium sporozoites infection by targeting the host cell

Abstract

There is a great need of new drugs against malaria because of the increasing spread of parasite resistance against the most commonly used drugs in the field. We found that monensin, a common veterinary antibiotic, has a strong inhibitory effect in Plasmodium berghei and P. yoelii sporozoites hepatocyte infection in vitro. Infection of host cells by another apicomplexan parasite with a similar mechanism of host cell invasion, Toxoplasma tachyzoites, was also inhibited. Treatment of mice with monensin abrogates liver infection with P. berghei sporozoites in vivo. We also found that at low concentrations monensin inhibits the infection of Plasmodium sporozoites by rendering host cells resistant to infection, rather than having a direct effect on sporozoites. Monensin effect is targeted to the initial stages of parasite invasion of the host cell with little or no effect on development, suggesting that this antibiotic affects an essential host cell component that is required for Plasmodium sporozoite invasion.Malaria, one of the most important parasitic diseases in humans, remains one of the major infectious diseases worldwide (Fauci, 2008). Considering the increasing problem of drug resistance in the parasite, there is an urgent need to identify new molecules with antimalarial activity. Since malaria affects mainly populations in developing countries who cannot afford most available treatments, the cost effectiveness analysis should be one prevalent paradigm taken into consideration when developing novel antimalarial therapies.The liver stage is the initial step of natural malaria infection in mammals, which is initiated when a mosquito inoculates Plasmodium sporozoites into the skin of the host. The sporozoites migrate in the dermis, reach blood vessels and are carried rapidly via the bloodstream to the liver, where they invade hepatic parenchymal cells and begin a period of asexual reproduction, producing exo-erythrocytic forms (EEFs) (Ejigiri and Sinnis, 2009). Upon maturation, infected hepatocytes release merozoites that invade erythrocytes, initiating the blood stage of the disease. Inhibitors of Plasmodium growth in the liver assume a particular relevance as prophylactic agents, but the list of applied drugs is very limited (Fauci, 2008).Monensin is a Na + ionophore that exchanges specifically Na + for H + , resulting in elevated cytosolic Na + concentration and pH (Mollenhauer et al., 1990 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptSpreptomyces cinnamonensis, is a w...

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

“…Our data show that salinomycin, monensin, and nigericin are very active in vitro against a number of P. falciparum isolates, including drug-resistant strains, in accordance with other reports (16,(29)(30)(31)(32)(33). Importantly, we also show that these molecules possess in vitro nanomolar activity against mature P. falciparum stage IV and V gametocytes and against P. berghei ookinetes, the earliest development stage in the mosquito vector.…”

“…Here, we demonstrate that ionophores inhibit the viability of stage IV and V gametocytes, as already described for all stages of asexual parasites (14). In addition, there is evidence that salinomycin and monensin are effective against liver stages, both in vitro (HepG2 cells infected by P. berghei sporozoites) and orally in P. berghei-infected C57BL/6 mice in vivo (32,33). Unlike many reference drugs, like DHA (28,45), salinomycin was more active on mature (stage IV and V) than young (stage II and III) gametocytes, which reinforces the transmission-blocking potential of this molecule.…”

“…Recent reports highlighted their activity against Trypanosoma brucei, Toxoplasma gondii, and cytomegalovirus (33)(34)(35)(36). Considerable attention has been devoted recently to salinomycin and derivatives due to their selective activity against tumor stem cells (13,37,38).…”

Preparation and Characterization of Monensin Loaded PLGA Nanoparticles: <I>In Vitro</I> Anti-Malarial Activity Against Plasmodium Falciparum

“…Its synthetic and semi synthetic derivatives are reported to have antimalarial activities that are executed by disruption of ionic gradients in the malaria parasite. [9][10][11][12] In recent reports by Mahmoudi et al 13 and Leitao et al 14 monensin has been shown active against the hepatocytic stages of malaria parasites. 13 14 Despite its strong potential as an antimalarial its extreme hydrophobic nature hinders its application in therapy.…”

“…[9][10][11][12] In recent reports by Mahmoudi et al 13 and Leitao et al 14 monensin has been shown active against the hepatocytic stages of malaria parasites. 13 14 Despite its strong potential as an antimalarial its extreme hydrophobic nature hinders its application in therapy. Being lipophilic in nature, it has a short half-life and therefore needs to be formulated in a suitable drug delivery system to improve its applicability in antimalarial therapy.…”