Researchers from the Antimicrobial Resistance (AMR) Interdisciplinary Research Group (IRG) at Singapore-MIT Alliance for Research and Technology (SMART), in collaboration with the Massachusetts Institute of Technology, Columbia University Irving Medical Center and Nanyang Technological University (NTU), Singapore, have identified a link between malaria parasites developing resistance to antimalarial drugs.
Affecting around 249 million people globally in 2022, malaria is a mosquito-borne disease that occurs when parasites spread to humans through the bites of infected Anopheles mosquitoes.
Specifically focusing on an antimalarial drug known as artemisinin (ART), researchers used a cellular process called transfer ribonucleic acid (tRNA) modification – a mechanism which allows cells to respond rapidly to stress by altering RNA molecules within a cell.
ART-based combination therapies are a first-line treatment for patients with uncomplicated malaria and help reduce the number of parasites during the first three days of treatment, in combination with a partner drug that eliminates the remaining parasites.
However, Plasmodium falciparum, the deadliest species of Plasmodium that causes malaria, has developed partial resistance to ART, particularly in Southeast Asia and Africa.
Published in Nature Biology, researchers investigated the role of epitranscriptomics, RNA modifications within a cell, in influencing drug resistance in malaria using advanced technology and techniques developed by SMART.
After comparing and isolating the drug-sensitive and drug-resistant malaria parasites, the analysis revealed changes in the tRNA modifications of drug-resistant parasites, which were linked to both increased and decreased translation of specific genes in parasites.
Researchers identified the altered translation process as a key underlying mechanism for the increase in drug resistance and also demonstrated how microbes and cancer cells can exploit the normal function of RNA modifications, causing toxic effects of drugs and other therapeutics.
Peter Preiser, co-lead principal investigator, SMART AMR and professor, molecular genetics and cell biology, NTU Singapore, commented: “This discovery reveals how drug-resistant parasites exploit epitranscriptomic stress response mechanisms for survival, which is particularly important for understanding parasite biology.”
