Abstract
The emerging spread of drug-resistant malaria parasites highlights the need for new antimalarial agents. This study evaluated the growth-inhibitory effects of sparsomycin (Sm), a peptidyl transferase inhibitor, against Plasmodium falciparum 3D7 (chloroquine-sensitive strain), P. falciparum K1 (resistant to multiple drugs, including chloroquine), P. yoelii 17XNL (cause of uncomplicated rodent malaria) and P. berghei ANKA (cause of complicated rodent malaria). Using a fluorescence-based assay, we found that Sm exhibited half-maximal inhibitory concentrations (IC50) of 12.07 and 25.43 nM against P. falciparum 3D7 and K1, respectively. In vitro treatment of P. falciparum 3D7 with Sm at 10 or 50 nM induced morphological alteration, blocked parasites in the ring state and prevented erythrocyte reinvasion, even after removal of the compound. In mice infected with P. yoelii 17XNL, the administration of 100 μg/kg Sm for 7 days did not affect parasitemia. Meanwhile, treatment with 300 μg/kg Sm resulted in a significantly lower parasitemia peak (18.85%) than that observed in the control group (40.13%). In mice infected with P. berghei ANKA, both four and seven doses of Sm (300 μg/kg) prolonged survival by 33.33%. Our results indicate that Sm has potential antiplasmodial activities in vitro and in vivo, warranting its further development as an alternative treatment for malaria.
Highlights
Malaria is a mosquito-borne infectious disease caused by protozoan parasites of the genus Plasmodium
Microscopic Analysis of Parasitemia and Morphology of P. falciparum 3D7 Treated with Sm In Vitro
The cytotoxicity of Sm against human foreskin fibroblasts (HFFs) was confirmed with a CC50 of 1.14 ± 0.03 μM, resulting in selectivity indices (SIs) of 94.45 (3D7) and 44.83 (K1)
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. One of the threats to efforts to eradicate malaria is the emergence of drug-resistant parasites [3]. The spread of multidrug-resistant malaria parasites is broadly caused by four factors, i.e., mutation and/or amplification of the target(s), stress response-based survival mechanisms and removal or sequestration of drugs and detoxifications [5]. Pharmaceutics 2022, 14, 544 library consisting of natural products and natural-product derivatives, curated by the Institute of Microbial Chemistry. From this screening, sparsomycin was stood out to exhibit antiplasmodial activity at the nanomolar scale and was further evaluated in this study. Considering the effects of Sm on protein translation, the in vitro inhibitory activity of Sm against the most common and deadliest human malaria parasite, P. falciparum (3D7 and K1) [15], was evaluated. To confirm the in vitro results, the effects of Sm were evaluated in vivo using two rodent malaria parasites with different virulence characteristics, P. yoelii 17XNL and P. berghei ANKA, respectively, for uncomplicated/non-lethal and complicated/lethal strains [17]
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