Large-scale cell-based screening campaigns have tested over 8 million compounds against the blood stage of P. falciparum, yielding thousands of chemically diverse active drug scaffolds. However, prioritization of compounds that may have novel mechanisms of action or that are not easily amenable to the generation of resistance can be challenging.
The Lee group therefore developed new molecular genetics approaches that harness CRISPR/Cas to enable rapid systems-level analysis of antimalarial compound action, including the identification of potential targets or mechanisms of resistance, cross-resistance profiles, and fitness costs associated with resistance.
Their novel tools have enabled in-depth validation of new drug targets and detailed biological investigation of specific genes or gene families. In addition, they use these tools to perform unbiased genetic screens, in the hope of assigning roles to the large number of parasite genes of unknown function, including lncRNAs about which little is known. The group also explore ways of adapting the RNA-guided CRISPR/Cas system for genome editing and gene regulation in the parasite.