A recent study has identified a connection between the ability of malaria parasites to resist antimalarial drugs, particularly artemisinin (ART), through transfer Ribonucleic acid (tRNA) modification. This process enables cells to adapt quickly to distress by modifying RNA within the cell. The findings of this study provide information on how malaria parasites react to drug-induced stress and resistance development, leading the path for innovative drug development to counter resistance (1^✔ ✔Trusted Source
tRNA modification reprogramming contributes to artemisinin resistance in Plasmodium falciparum

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This study was conducted by researchers at the Antimicrobial Resistance (AMR) Interdisciplinary Research Group (IRG) at Singapore-MIT Alliance for Research and Technology (SMART), MIT’s research entity in Singapore, in association with Massachusetts Institute of Technology (MIT), Columbia University Irving Medical Center (CUIMC), and Nanyang Technological University (NTU) Singapore.

Purpose of the Study and Cause for Resistance to Drugs

In 2022, malaria, a disease spread by mosquitoes, affected 249 million people worldwide and claimed 608,000 lives. The first-line treatment for people with uncomplicated malaria includes ART-based combination medicines, which mix ART derivatives with a synergetic medication. During the first three days of treatment, the ART medicine helps to lower the parasite count, followed by the effect of the synergetic medication which gets rid of the remaining parasites. However, there is a growing concern regarding the development of partial resistance to ART by Plasmodium falciparum (P. falciparum), the most lethal species of Plasmodium responsible for causing malaria in humans. This partial resistance has become prevalent in Southeast Asia and has now been identified in Africa.

Study Details and How it Would Help in Future

The researchers reported their groundbreaking finding in a paper titled “tRNA modification reprogramming contributes to artemisinin resistance in Plasmodium falciparum,” which was published in the journal Nature Microbiology. This modification affects a single tRNA, a small RNA molecule involved in converting genetic information from RNA to protein, and gives the malaria parasite resistance to medication. The paper explains how tRNA mutation can change the parasite’s protein expression profile, increasing its resistance to the treatment, and altering the parasite’s reaction to ART, helping it survive ART-induced distress. When ART-based combination therapies are used, the elimination of malaria parasites is delayed due to partial resistance to ART, which reduces their efficacy and increases the risk of treatment failure.

Jennifer L. Small-Saunders, Assistant Professor of Medicine in the Division of Infectious Diseases at CUIMC and first author of the paper stated, “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. This discovery paves the way for new strategies to combat this growing global threat,”.

The researchers used innovative tools and methods for epitranscriptomics, the science behind RNA modifications within a cell, created at SMART, and how drug resistance in malaria is influenced by epitranscriptomics. The process involved separating the tRNA and identifying the various changes that are present using mass spectrometry. The drug-sensitive and drug-resistant malaria parasites were separated; some of them were subjected to ART treatment, while the control group received no treatment at all. The study showed that the drug-resistant parasites had alterations in tRNA, which were associated with either enhanced or decreased gene translation in the parasites.

It was noted that the modified translation procedure was the fundamental mechanism behind the rise in drug resistance. This finding further enhances knowledge of how microorganisms and cancer cells manipulate RNA modifications to counteract the harmful impacts of medications and other treatments.

Peter Dedon, Co-Lead Principal Investigator at SMART AMR, Professor at MIT, and one of the authors of the paper stated, “Our research, the first of its kind, shows how tRNA modification directly influences the parasite’s resistance to ART, highlighting the potential impact of RNA modifications on both disease and health. 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,”.

Peter Preiser, Co-Lead Principal Investigator at SMART AMR, Professor of Molecular Genetics & Cell Biology at NTU Singapore, and one of the authors of the paper added, “At SMART AMR, we’re at the forefront of exploring epitranscriptomics in infectious diseases and antimicrobial resistance. Epitranscriptomics is an emerging field in malaria research and plays a crucial role in how malaria parasites develop and respond to stress. This discovery reveals how drug-resistant parasites exploit epitranscriptomic stress response mechanisms for survival, which is particularly important for understanding parasite biology,”.

This research provides a basis for the development of more efficient tools to study RNA modifications and their role in resistance, while at the same time opening up new paths into drug development. Currently, there is a lack of research on RNA-Modifying Enzymes; they are attractive targets for the development of new and more efficient drugs and treatments due to their association with resistance. By blocking the parasite’s ability to manipulate these modifications, drug resistance can be prevented. The scientists at SMART AMR are actively researching and developing therapies that target RNA modifications in viruses, bacteria, parasites, and cancer.

Reference:

1. tRNA modification reprogramming contributes to artemisinin resistance in Plasmodium falciparum – (https://pubmed.ncbi.nlm.nih.gov/38632343/)

Source-Medindia