PLoS Biol. 9, e1001138 (2011)

Credit: JOSEPH DERISI

The apicoplast in the malaria-causing Plasmodium spp. is an organelle that is thought to be a remnant of a red algae symbiont. Despite the loss of its photosynthetic capability and most of its genome during evolution, loss of this organelle is lethal during both the liver and blood stages of the parasite life cycle, so it must be inherited at each cell division. Fosmidomycin, known to kill blood-stage parasites, is an inhibitor of the prokaryotic pathway for synthesis of isoprenoid precursors. Yeh et al. have now further explored this biosynthetic pathway as a malarial drug target and found that one of its precursors, isopentenyl pyrophosphate (IPP), was sufficient to rescue the toxic effect of fosmidomycin. Antibiotics such as chloramphenicol or doxycycline that target transcription or translation also block apicoplast gene expression, and this causes a 'delayed-death' phenotype: the treated parasites themselves are not affected, but their progeny lack apicoplasts and ultimately die. IPP could also rescue this phenotype. The parasites live far beyond the first generation after IPP rescue, despite their lack of apicoplasts and apicoplast functions, which include protein import and processing. These results suggest that production of isoprenoid precursors is the only essential function of the malarial apicoplast during the replicative (blood) stage of the parasite, and they highlight the potential of developing drugs against this machinery to target the apicoplast and parasite replication.