Combinatorial Effects of Monensin in Liposome Formulations with Antimalarial Drugs Against Blood Stages of Plasmodium falciparum in Culture and P. berghei Infection

Abstract

Background: Monensin is a broad spectrum polyether antibiotic produced by Streptomyces cinnamonensis. It is widely used as veterinary medicine in the treatment of coccidiosis. Objective: The goal of this study was to assess the antimalarial efficacy of monensin in liposomal form in combination with potent antimalarial drugs like chloroquine, piperaquine, or FR900098 in free form under in vitro and in vivo condition. Method: In vitro drug sensitivity assay for different drug combinations against blood stages of chloroquine susceptible (3D7) and chloroquine resistant (INDO) strains of Plasmodium falciparum in culture was assessed by [3H]-hypoxanthine incorporation assay. In vivo efficacy was evaluated using the standard 4-day Peters’ test in established mice models of both Plasmodium berghei NK65 and lethal strain of P. berghei ANKA. Results: Our results indicate that monensin exhibits superior efficacy than partner antimalarial drugs tested. The drug combinations between monensin/chloroquine, monensin/ piperaquine, and monensin/FR900098 showed synergistic to additive action, at their 50- percent inhibitory concentrations (IC50s) against P. falciparum strains in culture. Monensin in liposomal formulations in combination with subcurative doses of partner antimalarial drugs effectively reduced parasitic burden in P. berghei infected mice than comparable doses of antimalarial drugs used alone. Conclusion: Our results demonstrate that liposomal monensin in combination with partner antimalarials (chloroquine, piperaquine or FR900098) showed positive interactions with enhanced parasite killing on P. falciparum strains and P. berghei infection in murine model. This approach may provide a promising chemotherapeutic regimen at lower doses for treating human malarial infections. Keywords: Drug combinations, liposome monensin, plasmodium, antimalarials, chemotherapy.