SMART study reveals mechanism driving drug resistance in malaria parasite

New Delhi: A study conducted by researchers from the Antimicrobial Resistance (AMR) Interdisciplinary Research Group (IRG) at Singapore-MIT Alliance for Research and Technology (SMART) has identified a crucial mechanism driving drug resistance in malaria parasites.

Collaborating with Massachusetts Institute of Technology (MIT), Columbia University Irving Medical Center (CUIMC), and Nanyang Technological University, Singapore (NTU Singapore), the study sheds light on how a cellular process known as transfer Ribonucleic acid (tRNA) modification influences the malaria parasite’s ability to develop resistance to artemisinin-based combination therapies (ACTs), the frontline treatment for malaria. 

In a recent study published in Nature Microbiology, titled “tRNA modification reprogramming contributes to artemisinin resistance in Plasmodium falciparum,” researchers unveiled a change in a specific tRNA molecule, crucial in translating genetic information from RNA to protein, enabling the malaria parasite to withstand drug-induced stress. This alteration in tRNA modification affects the parasite’s response to ART, enhancing its ability to survive ART-induced stress by modifying its protein expression profile. Consequently, ART partial resistance results in a delayed eradication of malaria parasites post-treatment with ART-based therapies, rendering these treatments less effective and susceptible to failure.

Malaria, a disease transmitted by mosquitoes, afflicted approximately 249 million individuals worldwide and led to 608,000 deaths in 2022. To combat this, ART-based combination therapies have been pivotal as first-line treatments for uncomplicated malaria cases. These therapies, comprising ART derivatives and partner drugs, work by initially reducing parasite numbers over three days, with the partner drug subsequently eliminating remaining parasites. However, Plasmodium falciparum, the deadliest strain of the malaria parasite, has been increasingly displaying partial resistance to ART, a phenomenon observed notably across Southeast Asia and now in Africa.

Lead author Jennifer L. Small-Saunders, Assistant Professor of Medicine at CUIMC, highlighted the critical importance of the study’s findings in addressing the growing threat of malaria drug resistance. “Malaria’s growing drug resistance to artemisinin, the current last-line antimalarial drug, is a global crisis that demands new strategies and therapeutics. The mechanisms behind this resistance are complex and multifaceted, but our study reveals a critical link. We found that the parasite’s ability to survive a lethal dose of artemisinin is linked to the downregulation of a specific tRNA modification.” she said.

The research, conducted using advanced epitranscriptomic analysis techniques developed at SMART, uncovered changes in tRNA modifications in drug-resistant parasites compared to drug-sensitive ones. These alterations in RNA modifications were found to influence the translation of specific genes in the parasites, ultimately leading to increased drug resistance. 

Co-author Peter Dedon, Co-Lead Principal Investigator at SMART AMR and Professor at MIT, emphasized the significance of RNA modifications. “While RNA modifications have been around for decades, their role in regulating cellular processes is an emerging field. Our findings highlight the importance of RNA modifications for the research community and the broader significance of tRNA modifications in regulating gene expression,” he stated.

Peter Preiser, Co-Lead Principal Investigator at SMART AMR and Professor of Molecular Genetics & Cell Biology at NTU Singapore, underscored the implications of the study for understanding parasite biology and developing new treatments. “This discovery reveals how drug-resistant parasites exploit epitranscriptomic stress response mechanisms for survival, which is particularly important for understanding parasite biology,” he noted.

The study lays the groundwork for the development of novel therapeutic strategies and enhance the effectiveness of existing antimalarial drugs by disrupting the parasite’s ability to manipulate tRNA modifications. The research is supported by the National Research Foundation (NRF) Singapore under its Campus for Research Excellence And Technological Enterprise (CREATE) programme.