Access to large phenotypic screens has enabled the discovery of many compounds which can kill malaria parasites and have a good safety profile. Translating these findings into new antimalarial drugs faces a number of challenges. Finding the mode of action of these compounds can help in focusing efforts to develop the most promising antimalarials. Such knowledge can also help in designing new combination therapies by targeting discrete pathways in the pathogens which can overcome the problem of emerging drug-resistance.
In this project, we investigated the mode of action of 11 potent antimalarial compounds obtained from the Medicines for Malaria Venture and the Open Source Malaria project.
Using a medium-throughput microplate-based method, we performed untargeted metabolomics analyses of Plasmodium falciparum parasites treated with test compounds. Data was processed using the in-house IDEOM (IDEntification Of Metabolites) analysis pipeline followed by multivariate statistical analyses.
The unbiased metabolomics approach revealed significant metabolic perturbations associated with the most potent compounds and identified the most likely pathways targeted by each compound. The major metabolic pathways which were found to be targeted were pyrimidine biosynthesis, glycolysis, phospholipid metabolism and haemoglobin degradation. Multivariate analyses revealed that some novel compounds targeted the same biochemical pathways as two known anti-malarials, Atovaquone and Cipargamin. Interestingly, compounds showing similar biochemical activities did not always have similar chemical structures.
This study showed that a simple and efficient metabolomics assay can rapidly reveal the biochemical basis of the mode of action of newly discovered antimalarial compounds. This information can be used for prioritising compounds before progressing them through the optimization pipeline and further development.