A new study sheds light on why Plasmodium falciparum, the deadliest malaria parasite, is developing resistance to Artemisinin (ART)-based combination therapies — the first-line treatments for uncomplicated malaria.

Researchers say the parasite performs a cellular process called transfer Ribonucleic acid (tRNA) helping it survive the stress induced by ART and making it more resistant to the drug.

Healthcare systems across Africa are on high alert as malaria — a disease that afflicted 249 million people and caused 608,000 deaths globally in 2022 — continues to evolve.

ART-based combination therapies have been crucial in reducing malaria cases and fatalities. However, partial resistance to ART has been spreading from Southeast Asia to Africa, posing a threat of treatment failure and delays in eradicating the malaria parasite.

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The emergence of artemisinin partial resistance (ART-R) already reported in Rwanda, Uganda, and Eritrea is causing concern. In Tanzania, a nationwide molecular malaria surveillance conducted in 2021 revealed a high prevalence of the Kelch13 (K13) 561H mutation in Plasmodium falciparum near the borders with Rwanda and Uganda.

This discovery, published in Nature Microbiology last week, helps in understanding of how malaria parasites respond to drug-induced stress and develop 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 down-regulation of a specific tRNA modification. This discovery paves the way for new strategies to combat this growing global threat,” said Jennifer Small-Saunders, Assistant Professor of Medicine in the Division of Infectious Diseases at CUIMC and first author of the paper.

The groundbreaking research provides critical insights into the mechanisms of drug resistance in malaria, offering hope for developing new strategies to combat this growing threat. As Africa continues to battle malaria, these findings represent a significant step towards more effective treatments and a more resilient healthcare system.

It is hoped that this discovery will help pave the way for new drugs to combat this resistance. The discovery was done by the Singapore-MIT Alliance for Research and Technology (SMART), in collaboration with MIT, Columbia University Irving Medical Centre, and Nanyang Technological University.

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“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,” said Jennifer Small-Saunders, Assistant Professor of Medicine in the Division of Infectious Diseases at CUIMC and first author of the paper.

This discovery sets the foundation for developing better tools to study RNA modifications and their role in resistance, opening new avenues for drug development.

By targeting RNA-modifying enzymes linked to resistance, researchers hope to develop new drugs that prevent the malaria parasite from manipulating these modifications, thereby stopping drug resistance from arising.

SMART AMR researchers are actively pursuing new therapeutics that target RNA modifications in various pathogens, including malaria.