The Race Against Resistance: How Kelch13 Mutations are Undermining Malaria Treatment
This is the third of three posts from participants in Baylor College of Medicine’s National School of Tropical Medicine Summer Institute program. View the first and second post.
Many people today assume that malaria is a relatively well-controlled disease, but in reality, it remains a major global health threat. Malaria is caused by the protozoan parasite Plasmodium species, with the deadliest species being Plasmodium falciparum, and is transmitted through the bite of an infected female mosquito. Malaria led to an estimated 249 million cases and 608,000 deaths in a single year globally. For decades, physicians relied on effective therapies to treat the disease. Yet, this disease continues to claim lives, particularly young children, pregnant women, travelers and individuals with no prior exposure to malaria.
For years, the standard treatment for malaria has been artemisinin-based combination therapies (ACTs). Artemisinin, the main ingredient, derived from the sweet wormwood plant, acts quickly, eliminating the parasites within hours. However, some of these parasites can survive an initial attack; therefore, a second drug in this therapy ensures that the remaining parasites are destroyed, preventing the infection from recurring. This two-step approach has made ACTs the most effective and efficient treatment for malaria thus far, significantly reducing mortality rates and helping people to recover quickly.
However, the effectiveness of ACTs is now being compromised as parasite resistance spreads, particularly in regions with high malaria burden. The parasite is evolving, and drug resistance is increasing in Southeast Asia and Sub-Saharan Africa. This isn’t just a medical challenge; it’s a race between modern science and microbial survival and if we don’t act quickly, malaria will win.
What happens when ACTs stop working at optimal levels?
Malaria resistance first emerged in Southeast Asia and has since emerged in other parts of the world, including Sub-Saharan Africa, where it has become particularly challenging. In addition to rising parasite resistance to ACTs, countries in Sub-Saharan Africa, like Rwanda, Uganda and Eritrea, also face some of the highest disease burdens due to limited healthcare infrastructure and high transmission rates. Growing resistance to ACTs is commonly linked to a gene within Plasmodium falciparum, known as Kelch13 (PfK13), an essential protein for parasite survival that aids in multiple intracellular processes. When the mutation occurs, it slows the parasite’s activity, impairing the efficacy of the malaria treatment (ACTs) and leading to delayed parasite clearance. Delayed parasite clearance means people who are infected stay infected for a longer period, and mosquitoes can spread the infection more easily to others.
Furthermore, the longer it takes for patients to recover clinically, the greater the financial strain experienced in resource-limited areas. And without faster drug development, delays in care and prevention will continue to compromise global malaria elimination efforts.
To address PfK13-associated ACT resistance, scientists are developing more effective treatments for parasite clearance and attempting to reduce the emergence of resistant P. falciparum globally. Clinical trials are underway for Triple Artemisinin Combination Therapies (TACTs), which add a third drug to the standard ACT to maximize parasite clearance.
Furthermore, to ensure treatments remain effective, genetic surveillance tools such as Droplet Digital PCR (ddPCR) technology are being developed to track parasite mutations regularly, allowing for the proactive adaptation of treatment protocols before resistance develops. By integrating alternative therapies, improving monitoring strategies, and creating effective interventions for early detection and prevention, researchers aim to establish sustainable treatment protocols that efficiently address resistance in this region and worldwide.
Understanding how Plasmodium falciparum evolves, especially through mutations in Kelch13, is crucial to reducing the global burden of malaria and staying ahead in the fight against it. By studying the mutations within this gene, researchers can develop stronger and more effective therapies that counteract artemisinin resistance, ensuring there is treatment for all patients worldwide. If researchers can identify how malaria parasites evolve and become resistant, we can better anticipate their adaptations, maintain drug efficacy and prevent the development of widespread resistance. Investing in more targeted medical therapies, tailored treatment strategies and preventive measures will reduce infection rates, hospitalizations and deaths in Sub-Saharan Africa and beyond. Moreover, such a proactive approach to early detection and treatment adaptation would alleviate pressure on already strained healthcare systems, especially in low-resource areas.
Suppose malaria spirals out of control in Sub-Saharan Africa due to failing treatments. In that case, the global community will face rising mortality, overwhelmed health systems, economic losses, and a dramatic setback in decades of malaria control. Without urgent intervention, delayed parasite elimination due to Plasmodium falciparum resistance will fuel long-term consequences of this disease, particularly in Sub-Saharan Africa, where 94% of global malaria cases occur.
Although global malaria incidence has generally declined, recent surges have occurred in certain regions such as Zimbabwe (increase to 111,998 cases in 2025 from 29,031 in 2024) and Botswana, where confirmed malaria cases reported through national surveillance rose to 2,223 in 2025 from 218 in 2024. This poses a serious threat to public health in Sub-Saharan Africa, jeopardizes the WHO’s 2030 malaria elimination target, and UN Sustainable Development Goal No. 3: ensuring good health and well-being for all. Future studies require real-world testing, such as field-based evaluations in malaria-endemic regions, to assess the long-term effectiveness of TACTs in malaria-burdened regions, including Sub-Saharan Africa and beyond.
Global health leaders cannot afford to wait any longer. Funding for drug development, advanced genetic surveillance and widespread malaria prevention efforts is critically needed. Without swift and sustained investment, ACT resistance will continue to intensify, weakening healthcare systems and reversing years of progress in global malaria elimination.
By Reena Yalamanchili
