Research
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 8 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. As part of these efforts, we are a member of the Malaria Drug Accelerator (MalDA) consortium (www.malariada.org), which aims to identify and validate new drug targets and develop early-lead inhibitors.
We are also 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 (Figure 1). This will allow us to prioritise compounds that may have novel mechanisms of action or that antagonise the generation of resistance. We work closely with MalDA partners and the Medicines for Malaria Venture to profile compound mode-of-action.
Figure 1. Antimalarial resistome barcode sequencing (AReBar) platform
We are also interested in understanding the influence of genetic background on the development of drug resistance and the maintenance of parasite fitness. To facilitate the evolution of resistance in the lab, we have generated a mutator parasite line with an elevated mutation rate (Figure 2).
Figure2: The “DNAPol” mutator parasite shows an elevated mutation rate and more rapid evolution of resistance under drug pressure (Kumpornsin et al., 2023, Nat Comm).
Developing molecular genetics approaches to interrogate gene function
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.
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, including lncRNAs about which little is known (Figure 3). We are exploring ways
of adapting the RNA-guided CRISPR/Cas system for genome editing and gene regulation in the parasite.
Figure 3: Manual annotation of lncRNAs in P. falciparum identifies >1000 novel lncRNAs (figure from Hoshizaki at al., 2022, BMC Genomics).