Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs

A mevalonate-independent pathway of isoprenoid biosynthesis present in Plas modium falciparum was shown to represent an effective target for chemothera py of malaria. This pathway includes 1-deoxy-D-xylulose 5-phosphate (DOXP) as a key metabolite. The presence of two genes encoding the enzymes DOXP sy nthase and DOXP reductoisomerase suggests that isoprenoid biosynthesis in P . falciparum depends on the DOXP pathway. This pathway is probably Located in the apicoplast. The recombinant P, falciparum DOXP reductoisomerase was inhibited by fosmidomycin and its derivative, FR-900098. Both drugs suppres sed the in vitro growth of multidrug-resistant P. falciparum strains. After therapy with these drugs, mice infected with the rodent malaria parasite P . vinckei were cured.