Epigenetics and Epitranscriptomics of of Drug Resistance
Our main research goal is to investigate novel epigenetic and epitranscriptomic aspects of drug resistance and stress tolerance in Plasmodium falciparum parasites.
Small-Saunders JL, Sinha A, Bloxham TS, Hagenah LM, Sun G, Preiser
PR, Dedon PC, Fidock DA. tRNA modification reprogramming contributes
to artemisinin resistance in Plasmodium falciparum. Nat Microbiol. 2024.
tRNA modification reprogramming and drug resistance
We are investigating the ways in which drug resistant Plasmodium falciparum can alter its tRNA modification profile to respond to stressors, including artemisinin. tRNA molecules are able to bias the translation of certain codons through modifications at the wobble base (position 34) which leads to differential translation of proteins. We have recently shown (Small-Saunders et. al. Nature Micro 2024) that this just-in-time epitranscriptomic stress response can be employed by artemisinin resistant parasites to aid in survival.
Sulfur tRNA modification pathways in Plasmodium
Artemisinin resistant Plasmodium falciparum can use alterations in sulfur tRNA modifications to alter its survival to drug pressure (Small-Saunders et. al. Nature Micro, 2024). We are investigating the biosynthetic pathways of these modifications and how their alteration can lead to parasite survival.
Epigenetic mechanisms of parasite quiescence
Although genetically identical, only a subset of artemisinin-resistant K13-mutant parasites are able to survive drug pulse. One aspect of this survival is entry into a quiescent state. We are interested in uncovering potential epigenetic mechanisms that can drive these parasites into or out of quiescence upon drug pressure and removal.
Discovery of epigenetic inhibitors
We are performing screens of existing and novel epigenetic and epitranscriptomic inhibitors for their antiplasmodial activity and probing their mechanisms of action. Inhibiting epigenetic and epitranscriptomic pathways that aid parasites in surviving drug treatment or stressors may lead to discovery of new parasite biology.
Funding
We are grateful for our support from governmental and philanthropic organizations.
