Drug resistance is one of the biggest threats to controlling malaria in endemic areas of the world. This issue was first recognized as early as the 1950s when chloroquine resistance was identified in Plasmodium falciparum. Since then, chloroquine resistance has spread to nearly all areas where malaria is endemic and P. falciparum has acquired resistances to all currently available drugs including sulfadoxine/pyrimethamine, mefloquine, and quinine.
Now, researchers have identified new mutations associated with the parasite’s decreased susceptibility to current treatments. By sequencing the whole genomes of Plasmodium falciparum from the blood of hundreds of infected people in Uganda, the team found that a cluster of genetic variants showed significantly decreased susceptibilities to the drugs most commonly used to treat malaria in Africa and the United States.
The findings were published in Nature Medicine in the paper, “Emergence and spread of Plasmodium falciparum PX1 polymorphisms associated with decreased susceptibility to antimalarials in Uganda.”
“It’s very concerning that these new mutations are spreading so rapidly—it tells us they are important to the parasite’s survival,” said Jeffrey Bailey, MD, PhD, associate professor of translational research and of pathology and laboratory medicine at Brown University. “Malaria still is a major killer, particularly in sub-Saharan Africa. As drug resistance continues to emerge, we worry it will undermine control of its spread and result in even more deaths for a large number of people there and beyond.”
Because of growing drug resistance, surveillance systems are being built to track known mutations in the pathogen as well as drug performance over time and identify biological markers of drug resistance.
“We knew that the parasites were changing so that over time, their susceptibility to malaria treatments was decreasing, and we wanted to know the exact genetic determinants of this shift,” said Karamoko Niaré, PhD, formerly a postdoctoral researcher in Bailey’s lab and now an adjunct assistant professor of pathology and laboratory medicine at Brown. “We decided to sequence the entire genome to get a better sense of what was going on.”
For the last two decades or so, the primary treatment for uncomplicated malaria in Uganda has been artemether-lumefantrine (AL), the most used artemisinin-based combination therapy (ACT) across sub-Saharan Africa. As of 2026, the Centers for Disease Control and Prevention has been recommending a longer course of therapy because standard doses failed to cure several travelers returning home, suggesting that the parasites are becoming less susceptible to treatment.
The researchers identified an area in the genome with 69 genes. More specifically, three specific mutations and two deletions were associated with decreased susceptibilities to the drugs artemisinin and lumefantrine (both components of AL) as well as the malaria drug mefloquine. The mutations most likely to drive this selection were found in a gene that encodes phosphoinositide-binding protein (PX1 protein) which is often found near another gene known to cause moderate resistance to the drug artemisinin.
This is the first time researchers have correlated a gene mutation with reduced susceptibility to multiple drugs used in the combination therapy for malaria.
“We didn’t have any validated molecular marker of lumefantrine resistance—we knew that there was a gene involved in partial resistance to artemisinin but couldn’t explain changes observed for lumefantrine,” Niaré said. “Our work identifies a molecular marker that could be used by surveillance studies to track the emergence and spread of reduced susceptibility to front-line malaria treatments across Africa. That’s a very important tool for public health.”
Since this effect was studied in the lab in parasites that had been collected from malaria patients, Bailey said future research should investigate how these mutant parasites impact clinical outcomes of malaria treatment with ACTs. While the authors found that the mutation was spreading rapidly in Uganda, how far it has spread beyond Uganda’s borders is unknown and needs to be examined.
The finding has major implications for sustaining an effective malaria treatment program, Bailey said. “It underscores the need to develop prediction models for when the drug will stop working altogether and also highlights the urgency to develop new drugs to treat malaria.”
