Isoprenoid Biosynthesis of the Apicoplast as Drug Target

In Plasmodium falciparum the biosynthesis of isoprenoids is achieved by the mevalonate-independent 1-deoxy-D-xylulose 5- phosphate (DOXP) pathway. The enzymes of the DOXP pathway are localised inside the plastid-like organelle (apicoplast). Fosmidomycin inhibits DOXP reductoisomerase, the second enzyme of this pathway. The antimalarial activity of fosmidomycin was established in vitro and in a rodent malaria model. Fosmidomycin alone or in combination with clindamycin was evaluated for the treatment of acute uncomplicated P. falciparum malaria in early phase II studies. Fosmidomycin monotherapy led to a fast parasite and fever clearance but was inefficient in radical elimination of the parasites. With the fosmidomycin-clindamycin combinations the cure ratio on day 28 was 100 % (10/10) with treatment durations of 5 and 4 days. The cure ratio was 90 % (9/10) with treatment duration of 3 days.