Abstract

The repeated emergence of antimalarial resistance underscores the importance of identifying new drug targets, as well as understanding the genetic architecture of current resistance pathways and any associated fitness costs. We have developed several genomics-based approaches that leverage CRISPR editing of the Plasmodium falciparum genome to validate causal resistance mutations and explore the essentiality and biological function of gene families as antimalarial targets. To more efficiently determine if compounds kill the parasite via known modes-of-action, we have generated a panel of barcoded parasite lines that encompass a wide spectrum of the known Plasmodium resistome, and have miniaturised a compound-screening assay to allow semi-automated liquid handling of parasite cultures. Competitive growth of drug-resistant lines also reveals the fitness cost of resistance. To overcome a bottleneck in evolution of resistance in the lab, we have also developed “mutator” parasite lines with an elevated mutation rate to increase the genetic complexity of parasite cultures. Finally, we are exploring whether non-coding mutations, specifically in lncRNAs, might also contribute to the parasite resistome. Collectively these approaches aim to accelerate the identification and validation of potential new targets, as well as understand the breadth of the parasite response to antimalarial challenge.