Inhibitors of the Nonmevalonate Pathway of Isoprenoid Biosynthesis as Antimalarial Drugs

TLDR

Plasmodium falciparum relies on a mevalonate‑independent isoprenoid biosynthesis pathway (DOXP) located in the apicoplast, making it a promising target for antimalarial chemotherapy. Fosmidomycin and its derivative FR‑900098 inhibit Pf DOXP reductoisomerase, suppress growth of multidrug‑resistant strains in vitro, and cure mice infected with P.

Abstract

A mevalonate-independent pathway of isoprenoid biosynthesis present in Plasmodium falciparum was shown to represent an effective target for chemotherapy 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 synthase 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 suppressed 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.