Nutrient Uptake and Metabolism - Project A2

Lipids as targets for antimalarial drugs 

Host lab: Alex Maier (ANU)

Partner labs: Kai Matuschewski (HUB), Edda Klipp (HUB), Melanie Rug (ANU) & Martin Blume (RKI)

Lipids – together with proteins and nucleid acids – are the major building blocks of cells. We have recently determined the lipid composition of the different life cycle stages of Plasmodium falciparum and Plasmodium berghei. Based on this data we will now determine key molecules that are important for lipid import and metabolism and explore their role and potential as drug targets. A bioinformatic overview obtained in silico will guide us to identify rate limiting steps in the lipid metabolism. These predictions will be verified using transgenic approaches using CRISPR/Cas9 and various tagging strategies. Our approaches will also determine the localization, function and importance of these enzymes and transporters for the survival of the malaria parasites.

Changes in the lipid composition of red blood cells infected with transgenic parasites will be determined via mass-spectroscopy. Mass-spectroscopy will also be used to determine the fate of labelled precursor molecules and their distribution in the network of lipid metabolites.

In parallel we will chemically target enzymes that are essential and determine the suitability of these compounds as antimalarials.

The rodent malaria system will not only act as a model to determine the effect of lipid-targeting compounds in vivo, but it will also highlight species-specific adaptions that have been evolved in response to different host environments.

Keywords: malaria, lipid metabolism, drug-able molecules, enzymes, transporters

Keywords Methods: reverse genetics, CRISPR/Cas9, endogenous tagging, fluorescent microscopy, cell culture, metabolic modelling