Cellular redox balance plays an essential role in pathogenic microorganisms. Centrally involved as the main NADPH suppliers are the enzymes glucose 6-phosphate dehydrogenase (G6PD) and 6-phosphogluconolactonase (6PGD) of the pentose phosphate pathway (PPP). The enzymes differ structurally from their human orthologues and are considered promising drug targets. Our project originated from a high-throughput screen of the NIH collection against Plasmodium falciparum G6PD (PfG6PD), resulting in the identification of the highly selective PfG6PD inhibitor, SBI-750. Notably, this inhibitor demonstrated remarkable activity in the low nanomolar range following structure-activity relationship (SAR) studies and lead optimization. The primary goal of our project is to extend this successful concept to other parasitic strains, specifically Leishmania and Schistosoma, with the objective of identifying potent drug candidates for the treatment of infections caused by these parasites. Commencing with the recombinant production and comprehensive biochemical characterization of G6PD and 6PGD from Leishmania and Schistosoma spp., we achieved a significant milestone by elucidating the first 3D crystal structure of the leishmanial enzymes. Leveraging these structural insights, we conducted an in silico screen of small molecules, resulting in the identification of initial hits, that are currently undergoing hit-to-lead optimization. Concurrently, our collaboration with Novartis NIBR has yielded additional hits through a high-throughput screening approach, enriching our pool of potential drug candidates.