Chemical Rescue of Malaria Parasites Lacking an Apicoplast Defines Organelle Function in Blood-Stage Plasmodium falciparum

Ellen Yeh,Joseph L Derisi,Boris Striepen

doi:10.1371/journal.pbio.1001138

Abstract

Author SummaryMalaria caused by Plasmodium spp parasites is a profound human health problem that has shaped our evolutionary past and continues to influence modern day with a disease burden that disproportionately affects the world's poorest and youngest. New anti-malarials are desperately needed in the face of existing or emerging drug resistance to available therapies, while an effective vaccine remains elusive. A plastid organelle, the apicoplast, has been hailed as Plasmodium's “Achilles' heel” because it contains bacteria-derived pathways that have no counterpart in the human host and therefore may be ideal drug targets. However, more than a decade after its discovery, the essential functions of the apicoplast remain a mystery, and without a specific pathway or function to target, development of drugs against the apicoplast has been stymied. In this study, we use a simple chemical method to generate parasites that have lost their apicoplast, normally a deadly event, but which survive—“rescued” by the addition of an essential metabolite to the culture. This chemical rescue demonstrates that the apicoplast serves only a single essential function, namely isoprenoid precursor biosynthesis during blood-stage growth, validating this metabolic function as a viable drug target. Moreover, the apicoplast-minus Plasmodium strains generated in this study will be a powerful tool for identifying apicoplast-targeted drugs and as a potential vaccine strain with significant advantages over current vaccine technologies.

Highlights

The discovery of a plastid organelle, the apicoplast, in Plasmodium spp. and other Apicomplexa parasites instantly made it a key target in the development of new therapies against these pathogens [1,2,3]
Malaria caused by Plasmodium spp parasites is a profound human health problem that has shaped our evolutionary past and continues to influence modern day with a disease burden that disproportionately affects the world’s poorest and youngest
We use a simple chemical method to generate parasites that have lost their apicoplast, normally a deadly event, but which survive—‘‘rescued’’ by the addition of an essential metabolite to the culture. This chemical rescue demonstrates that the apicoplast serves only a single essential function, namely isoprenoid precursor biosynthesis during blood-stage growth, validating this metabolic function as a viable drug target

Summary

Introduction

The discovery of a plastid organelle, the apicoplast, in Plasmodium spp. (responsible for 250 million cases of human malaria each year) and other Apicomplexa parasites instantly made it a key target in the development of new therapies against these pathogens [1,2,3]. The need for new anti-malarials is urgent given the documentation of developing resistance to the current last-line therapy in the deadliest species, P. falciparum [4]. Several features of this organelle make it both biologically fascinating and an attractive therapeutic target. During the course of evolution, the apicoplast has lost its photosynthetic function and transferred most of its genome to the nucleus, requiring a dedicated protein targeting pathway to localize the majority of its over 500 gene products into the organelle [7,8]. In Plasmodium, apicoplast function is necessary for both intraerythrocytic and intrahepatic development in the human host [9,10]. Whether the apicoplast is required for sexual stage development in the mosquito is currently unknown [11,12,13,14]

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Conclusion