Malaria continues to be one of the deadliest
infectious diseases and a global health menace. The emergence and spread of
drug-resistant strains of
malaria parasites have further made the process of disease management grimmer. Thus, there is an urgent need to identify promising
antimalarial strategies that can target the blood stages as well as block parasite transmission.
Maduramicin is one such
ionophore selected out of a recent screen of gametocytocidal compounds that exhibit potent antiplasmodial activity. However,
maduramicin's strong hydrophobic nature and associated toxicity restrict its application in
chemotherapy. To alleviate this problem, we have developed a liposomal formulation loaded with the
ionophore maduramicin for the treatment of
chloroquine sensitive and resistant
Plasmodium infections. Here, we show that
maduramicin in PEGylated liposomal formulations displayed enhanced antiplasmodial activity in vitro compared to free
maduramicin. Significantly, four consecutive doses of 1.5 mg kg-1
body weight of PEGylated
maduramicin loaded
lipid vesicles completely cured cerebral and
chloroquine resistant murine models of
malaria without any obvious toxic effects and suppressed the key inflammatory markers associated with the progression of the disease. PEGylated liposomal
maduramicin also exhibited a prolonged plasma clearance rate, implying a greater chance of interaction and uptake by infected RBCs. Furthermore, we also provide evidence that the detrimental effect of liposomal
maduramicin on parasite survival is mediated by increased ROS generation and subsequent perturbation of parasite mitochondrial membrane potential. This study presents the first report to demonstrate the potent
antimalarial efficacy of
maduramicin liposomes, a strategy that holds promise for the development of successful therapeutic intervention against
malaria in humans.