Abstract The increased resistance of human malaria parasite Plasmodium falciparum to currently used drugs necessities the development of novel anti-malarials. In the present study, we examine the potential of erythritol, a sugar substitute, for therapeutic intervention that target a multifunctional transporter protein Plasmodium aquaglyceroporin ( Pf AQP) responsible for maintaining hydro-homeostasis. We show that erythritol effectively inhibited growth and progression of asexual blood stage malaria parasite by suppressing invasion and egress processes. It inhibited the liver stage (sporozoites) and transmission stage parasite (gametocytes) development that suggest its multi-stage, transmission-blocking potential. 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’. No Evans blue staining in treated mice indicated erythritol mediated protection of blood–brain barrier integrity in mice infected with P. berghei . Additionally, erythritol showed cytokine-modulating effect which suggest its direct effect on the host immune system. Our results of cellular thermal shift assay and ammonia detection assay demonstrate that erythritol binds with Pf AQP and reduce the amount of ammonia release across the parasite respectively. We performed functional complementation assays which suggest that Pf AQP expression in yeast mutant restores its growth in hyperosmotic conditions but showed reduced growth in the presence of erythritol, suggesting erythritol as an inhibitor of Pf AQP. Overall, our data bestow erythritol as a promising new lead compound with an attractive antimalarial profile and could possibly be combined with known drugs without losing its efficacy.

‘Erythritol’, a safe natural sweetener exhibits multi-stage anti-malarial activity by blocking <i>Plasmodium falciparum</i> membrane transporter ‘aquaporin’

‘Erythritol’, a safe natural sweetener exhibits multi-stage anti-malarial activity by blocking Plasmodium falciparum membrane transporter ‘aquaporin’