Fosmidomycin as an antimalarial agent

Abstract

The isoprenoid biosynthesis of Plasmodium falciparum, the causative agent of malignant tertiana malaria, solely depends on the mevalonate-independent 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway [also known as the 1-deoxy-d-xylulose 5-phosphate (DXP) pathway]. The enzymes of the MEP pathway of P. falciparum are located in a plastid-like organelle called the apicoplast. The growth of P. falciparum parasites is rapidly inhibited by fosmidomycin, an inhibitor of DXP reductoisomerase. The antimalarial activity of fosmidomycin has been substantiated in several clinical phase II studies. Most thoroughly, the treatment of malaria patients with a drug combination consisting of fosmidomycin and clindamycin has been investigated. With this combination, cure rates of approximately 90% were achieved after 3 days of treatment. In vitro studies revealed improved antimalarial activity of several fosmidomycin derivatives. At present, the compound FR-900098 represents the most promising derivative with respect to its low toxicity and proven activity in the P. vinckei mouse model.