Selective targeting of Plasmodium falciparum hexose transporter by phytochemical Ginsenoside Rg1 disrupts glucose metabolism and blocks development of parasite.

The emergence of resistance to first-line antimalarial therapies highlights the critical need for next-generation drugs that target distinct molecular pathways and employ novel mechanisms of action. Notably, the intra-erythrocytic parasite development is highly dependent on a sustained glucose supply as their fundamental energy source. Therefore, exploiting a "selective starvation" strategy by targeting the parasite's reliance on glucose metabolism, particularly through the Plasmodium falciparum hexose transporter (PfHT), which is critical for parasite survival, can serve as a promising therapeutic approach to combat multidrug-resistant Plasmodium parasites. Through molecular docking and a structure-based drug design approach, we identified a natural compound, Ginsenoside Rg1 (G-Rg1) from the Drug Bank database library, as a potential PfHT inhibitor. The PfHT specificity of G-Rg1 was validated using a yeast complementation model. Subsequently, to investigate the role of PfHT in drug-resistant Pf parasites, we investigated the stage-specific expression of PfHT in both artemisinin (ART)-sensitive and resistant Pf parasites and reported its elevated expression in resistant parasites, predicting its role in their survival. Notably, in vitro growth inhibition studies demonstrated that G-Rg1 effectively suppressed the growth of both ART-sensitive and resistant Pf parasites. Additionally, G-Rg1 potentiated the efficacy of dihydroartemisinin in combination and ring survival assays, indicating its potential to circumvent resistance mechanisms. G-Rg1 administration alone and in combination with ART, in Plasmodium berghei ANKA-infected mice, reduced parasite multiplication and increased mean survival time. Our findings support G-Rg1 as a promising candidate for drug development against malaria, highlighting the potential of targeting PfHT to combat drug-resistant malaria.