Novel antimalarial strategies using metabolomic network discovery

Malaria is a major global health issue affecting over half a billion people and resulting in 3-5 million deaths annually. This disease is caused by parasites of the genus Plasmodium with P. falciparum being the most lethal species. The host-pathogen relationship between Plasmodium and the host red blood cell is responsible for all clinical manifestations of the malaria disease and is a continuous 48-hour cycle that can be faithfully reproduced in the laboratory. Despite over a century of research on malaria, it continues to be a major health problem largely because drug-resistant parasites are on the rise, circumventing long-efficacious drug treatments. Thus, there is a renewed urgency to identify novel chemotherapeutics to treat this disease. This proposal aims to provide the first global analysis of the metabolic host-pathogen interactions for Plasmodium falciparum as a means to identify novel drug targets. The metabolic pathways encoded in any pathogen genome define the repertoire of chemical processes that it can autonomously regulate. All other metabolites must be taken up from the host cell or metabolized from precursors available through the host. Therefore, the host cell and pathogen are intimately linked through the reliance of the pathogen on the host for nutrients. The genome of P. falciparum suggests that this organism is biochemically unique: 60% of its genome encodes proteins never seen before in biology, and the remaining 40% contains very few of the fundamental metabolic genes found in almost all other eukaryotes. This indicates that the mechanism of interaction between Plasmodium and the host red blood cell may reveal novel metabolic enzymes that can provide new targets for pharmacological intervention. Using recently developed mass spectrometry techniques, we will quantitate metabolites in Plasmodium-infected cells and integrate these and other data to generate network interaction models revealing new biological insights into this deadly pathogen.