Sparsomycin Exhibits Potent Antiplasmodial Activity In Vitro and In Vivo

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.

Keywords: Plasmodium berghei; Plasmodium falciparum; Plasmodium yoelii; antiplasmodial; sparsomycin.

Figure 1

The structure of sparsomycin.

Figure 2

Representative morphology and parasitemia levels of parasites under no treatment (control) or sparsomycin (Sm) treatment (50 nM and 10 nM). (A) Parasite morphology after 1, 24, 48 and 72 h of incubation. The parasites in the treated group were retained in the ring stage, they were shrunken and they could not form trophozoites in the life cycle. Scale bar: 5 μm. (B) Parasitemia levels after 1, 24, 48 and 72 h of incubation. Parasitemia levels are presented as the mean of triplicate wells and the error bars represent standard deviations. *, significant (p < 0.05); ns, not significant (p > 0.05). The significance of differences in the level of parasitemia of Sm-treated cultures compared with control were analyzed by two-way ANOVA and a Tukey’s multiple comparison test.

Figure 3

Representative morphologies and parasitemia levels of parasites after 72 h exposure of growth under no treatment (control) or sparsomycin (Sm) treatment (50 and 10 nM). (A) Parasite morphologies after 96, 120 and 144 h incubation in the presence (unwashed) or absence (washed) of Sm. All parasites in the treated group were retained in the ring stage, they were shrunken and they could not form trophozoites in the life cycle. Scale bar: 5 μm. (B) Parasitemia levels after 96, 120 and 144 h of incubation in the presence (unwashed) or absence of Sm (washed). Parasitemia levels are presented as the mean of triplicate experiments and the error bars represent standard deviations. The significance of differences in the level of parasitemia of Sm-treated cultures compared with control were analyzed by two-way ANOVA and a Tukey’s multiple comparison test (*, significant at p < 0.05).

Figure 4

Effects of 7 days of sparsomycin (Sm) treatment on C57BL/6 mice infected with P. yoelii 17XNL. (A) Parasitemia levels after treatment with 100 μg/kg Sm and (B) parasitemia levels after treatment with 300 μg/kg following the inoculation of 1 × 10⁷ infected erythrocytes. Each group consisted of six mice. *: the significance of differences in the level of parasitemia in Sm-treated mice compared with control mice was analyzed by two-way ANOVA followed by Sidak’s multiple comparison test (p < 0.05).

Figure 5

Effects of (A) 4 or (B) 7 days of treatment with 300 μg/kg sparsomycin (Sm) on the survival of C57BL/6 mice infected with P. berghei ANKA. Mice were infected via inoculation with 1 × 10⁷ infected erythrocytes. Each group consisted of six mice. *, significant (p < 0.05); ns, not significant (p > 0.05). Survival rates were calculated using the log rank (Mantel–Cox) test.