Inhibition of GLUTs by WZB117 mediates apoptosis in blood-stage Plasmodium parasites by breaking redox balance

Like tumour cells, during intraerythrocytic stage, Plasmodium-infected erythrocytes rely completely on glucose absorption from the blood circulation for energy metabolism. Glucose is taken up by glucose transporter 1 (GLUT1) on human red blood cells (RBCs) and glucose transporter 4 (GLUT4) on rodent RBCs. Blood-stage parasites grow rapidly; therefore, infected red blood cells (iRBCs) need much more glucose for energy. In previous study, WZB117 (2-fluoro-6-(m-hydroxybenzoyloxy) phenyl m-hydroxybenzoate) inhibits GLUT1 by binding the exofacial sugar-binding site and inhibits the insulin-sensitive GLUT4 with greater potency than its inhibition of either GLUT1 or GLUT3. In our study, WZB117 effectively inhibit the growth of blood-stage parasites. Mechanistically, WZB117 inhibited the activity of GLUTs and perturbed the glycolysis. Therefore, decreasing the glucose level increased the redox oxidative species (ROS) level and induced oxidative stress and apoptosis. The spleen can more easily clear apoptopic iRBCs than nonapoptotic iRBCs, effectively relieving hepatosplenomegaly. These findings provide important insights into the crucial role of glucose transporters (GLUTs) in Plasmodium glucose uptake during intra-erythrocytic stage, as the inhibition of GLUTs block Plasmodium infection during the erythrocytic stage.