Lee Group

Malaria Parasite Drug Resistance

Archive Page

This page is maintained as a historical record and is no longer being updated.

The Lee research group moved to the University of Dundee in 2023. This page is being maintained as a historical record of the group’s work while at the Sanger Institute and is no longer being updated.

Marcus Lee’s group is interested in the molecular basis of drug resistance in the human malaria parasite Plasmodium falciparum, and in developing molecular genetics tools to interrogate gene function in this important pathogen.

Of the >5000 genes in the genome of the malaria parasite, a sizable number have unknown function and lack homologs outside of Plasmodium species. A deeper understanding of their roles and essentiality would provide biological insight as well as suggest new therapeutic targets.

Research Areas

Understanding the molecular basis for drug resistance

Antimalarial drug resistance is one of the most significant challenges facing malaria control, and resistance has developed to every major drug released to date. To identify new drugs, several large-scale screening campaigns have tested over 6 million compounds in cell-based screens against the blood stage of P. falciparum, yielding thousands of chemically diverse active drug scaffolds. However a major challenge is to leverage these compounds to identify targets that are either particularly vulnerable to perturbation, or refractory to resistance.

We are developing platforms that permit the rapid analysis of multiple aspects of antimalarial compound action, including the identification of potential targets or mechanisms of resistance, cross-resistance profiles, and fitness costs associated with resistance. This will allow us to prioritize compounds that may have novel mechanisms of action or that antagonise the generation of resistance.

Developing molecular genetics approaches to interrogate gene function

Advances in our ability to manipulate the parasite genome will be critical to any systematic investigation of Plasmodium biology. These applications include the in-depth validation of new drug targets and detailed biological investigation of specific genes or gene families.. In addition we are interested in developing tools for performing unbiased genetic screens, in the hope of assigning roles to the large number of parasite genes of unknown function. We are exploring ways of adapting the RNA-guided CRISPR/Cas system for genome editing and gene regulation in the parasite.