In Vitro Antimalarial Activity of Different Inhibitors of the Plasmodial Isoprenoid Synthesis Pathway

Previous studies have shown that fosmidomycin, risedronate, and nerolidol exert antimalarial activity in vitro. We included squalestatin, an inhibitor of the isoprenoid metabolism in Erwinia uredovora, and found that combinations of compounds which act on different targets of the plasmodial isoprenoid pathway possess important supra-additivity effects. Malaria expansion in some areas has been attributed to thefailure of vector-control policies and,mainly, to the increase of parasite resistance to drugs commonly used for its therapy (1). This alarming scenario has fuelled research in new antimalarial drugs, and, with the sequencing of parasite genomes, new poten-tial drug targets have emerged. Burrows et al. published a review discussing the strategies for designing the next generation ofmed-icines for malaria control (2). A metabolic pathway that may be a likely target for evaluating potential antimalarials is the isoprenoid pathway. The first intermediates are biosynthesized in the apico-plast, which is an organelle present in protozoan parasites of the subphylum Apicomplexa, including Plasmodia (3). We have previously demonstrated that the isoprenoid biosyn