New genetic mutations linked to malaria drug resistance discovered

Researchers searching for genetic clues to the growing problem of malaria drug resistance identified new mutations associated with the parasite's decreased susceptibility to current treatment.

By sequencing the whole genomes of malaria parasites from the blood of hundreds of infected people in Uganda, a team of researchers lead by scientists at Brown University found that a cluster of genetic variants in some parasites showed significantly decreased susceptibilities to the drugs most commonly used to treat malaria in Africa and the United States.

The findings of the federally funded study were published in Nature Medicine.

It's very concerning that these new mutations are spreading so rapidly - it tells us they are important to the parasite's survival. 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."

Dr. Jeffrey Bailey, study author, associate professor of translational research and of pathology and laboratory medicine, Brown University

Drug resistance often happens when treatments for bacterial, viral or parasitic illnesses are offered at a very large scale, as is the case of malaria treatment in Africa. Because of that, Bailey explained, surveillance systems are being built to track known mutations in the pathogen as well as drug performance over time.

Bailey's lab at Brown has been instrumental in building genomics systems to support the surveillance programs by sequencing DNA and tracking mutations and has received federal and foundation grants for this work in countries around Africa.

The surveillance projects tend to focus on identified biological markers of drug resistance, Bailey said. To discover clues to explain new susceptibilities, Karamoko Niaré, formerly a postdoctoral researcher in Bailey's lab, started to focus on whole-genome sequencing.

"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 Niaré, now an adjunct assistant professor of pathology and laboratory medicine at Brown, and first author of the publication. "We decided to sequence the entire genome to get a better sense of what was going on."

Treating malaria

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 of the malaria parasite encompassing 69 genes. Through additional genetic analyses, they found that a linked variant set comprising three specific mutations and two deletions was 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 a protein called PX1, or phosphoinositide-binding protein, which is often found near another gene product 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."

The newly discovered mutation should be integrated into the mutation tracking systems and further studied, Niaré said. 

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," Bailey said, "and also highlights the urgency to develop new drugs to treat malaria."

Melissa Conrad, an associate professor at Johns Hopkins University, supervised the work jointly with Bailey. The project was a collaboration with integral work from other investigators at the Infectious Disease Research Collaboration in Uganda, University of California, San Francisco, University of North Carolina at Chapel Hill, and University of Notre Dame.

The study was funded by the National Institutes of Health/National Institute of Allergy and Infectious Diseases (R01AI173557, K24AI134990, R01AI075045, U19AI089674, R01AI117001 and R01AI139179); the Medicines for Malaria Venture (RD/15/0001); and the Gates Foundation (INV-035751).