Inhibition of the Non-Mevalonate Isoprenoid Pathway by Reverse Hydroxamate Analogues of Fosmidomycin

The non-mevalonate (methylerythritol phosphate, MEP) pathway for isoprenoid biosynthesis is essential in Plasmodium spp.., but is absent in the human host. The pathway is a clinically validated antimalarial target on basis of studies with the antibiotic fosmidomycin, an inhibitor of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (Dxr, IspC), which catalyses the first committed step of the MEP-pathway. In this review, we report on reverse, hydroxamate-based fosmidomycin analogues, which are studied by enzyme kinetics, parasite growth inhibition and crystallography in order to identify compounds with enhanced antiplasmodial activity.