Selective targeting of Plasmodium falciparum hexose transporter by phytochemical Ginsenoside Rg1 disrupts glucose metabolism and block 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 parasites reliance on glucose metabolism, particularly through the Plasmodium falciparum hexose transporter (PfHT1), which is critical for parasite survival can serve as a promising therapeutic approach to combat multidrug-resistant Plasmodium parasites. Through molecular docking and structure-based drug design approach, we identified a natural compound, Ginsenoside Rg1 (G-Rg1) from drug bank database library, as a potential PfHT1 inhibitor. The PfHT1 specificity of G-Rg1 was validated using yeast complementation model. Subsequently, to investigate the role of PfHT1 in drug resistant Pf parasites we investigated the stage-specific expression of PfHT1 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 P. 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 PfHT1 to combat drug-resistant malaria.