'Erythritol', a safe natural sweetener exhibits multi-stage anti-malarial activity by permeating into Plasmodium falciparum through aquaglyceroporin channel

The increased resistance of human malaria parasite Plasmodium falciparum (Pf) to currently used drugs necessities the development of novel anti-malarials. Here, we examine the potential of erythritol, a sugar substitute for therapeutic intervention. Erythritol is a permeant of Plasmodium falciparum aquaglyceroporin (PfAQP) which is a multifunctional channel responsible for maintaining hydro-homeostasis. We show that erythritol effectively inhibited growth and progression of asexual blood stage malaria parasite, and effect invasion and egress pro-cesses. It also inhibited the liver stage (sporozoites) and transmission stage parasite (gametocytes) development. Interestingly, erythritol inhibited in vivo growth of malaria parasite in mouse experimental model. It was more effective in inhibiting parasite growth both in vivo and in vitro when tested together with a known anti-malarial 'artesunate'. Additionally, erythritol showed cytokine-modulating effect which suggests its direct effect on the host immune system. Ammonia detection assay demonstrated that erythritol uptake effects the amount of ammonia release across the parasite. Our functional complementation assays suggest that PfAQP expression in yeast mutant restores its growth in hyperosmotic conditions but showed reduced growth in the presence of erythritol. Osmotic lysis assay suggests that erythritol creates osmotic stress for killing the parasite. Overall, our data bestow erythritol as a promising lead compound with an attractive antimalarial profile and could possibly be combined with known drugs without losing its efficacy. We propose the use of erythritol based sweet candies for protection against malaria specially in children living in the endemic area.

Automated summary

The study shows that erythritol, a sugar substitute, has potential as a therapeutic intervention against drug-resistant malaria parasite Plasmodium falciparum. Erythritol effectively inhibits parasite growth and development, as well as invasion and egress processes. It also demonstrates inhibitory effects on liver stage and transmission stage parasites. In addition, erythritol has a cytokine-modulating effect and affects ammonia release across the parasite. The findings suggest that erythritol could be a promising lead compound for anti-malarial drugs and can be combined with existing drugs without losing efficacy.