A Brown University-led study has identified novel mutations in Plasmodium parasites that reduce susceptibility to artemisinin, lumefantrine and mefloquine, offering a potential new molecular marker for resistance surveillance across Africa.
Researchers have identified new genetic mutations in malaria parasites that are associated with reduced susceptibility to several drugs used to treat the disease, raising concerns about the spread of treatment resistance.
The study, led by scientists at Brown University, analysed the whole genomes of malaria parasites collected from the blood of hundreds of infected people in Uganda. The researchers identified a cluster of genetic variants associated with significantly reduced susceptibility to drugs commonly used to treat malaria in Africa and the United States.
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, Associate Professor of Translational Research and of Pathology and Laboratory Medicine at Brown University.
The findings could help researchers strengthen systems designed to detect emerging resistance before existing treatments become ineffective.
Finding resistance beyond known markers
Drug resistance can occur when medicines are used extensively, creating evolutionary pressure that favours pathogens able to survive treatment.
Malaria is a particular concern because of the scale of treatment across Africa. Surveillance programmes currently monitor known genetic markers of resistance alongside changes in drug performance.
Bailey’s laboratory has helped develop genomic systems for tracking malaria mutations across African countries. However, existing surveillance tends to focus on resistance markers that have already been identified.
Karamoko Niaré, formerly a postdoctoral researcher in Bailey’s lab, used whole-genome sequencing to search for previously unknown genetic changes.
“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.”
A potential new surveillance marker
The researchers identified a region containing 69 genes. Further analysis linked three mutations and two deletions with reduced susceptibility to artemisinin and lumefantrine, the two components of artemether-lumefantrine (AL), as well as the malaria drug mefloquine.
The mutations most likely to be driving this selection were found in a gene encoding PX1, or phosphoinositide-binding protein. The gene is often located near another gene associated with moderate artemisinin resistance.
This study is the first to link a genetic mutation with reduced susceptibility to multiple drugs used in malaria combination therapy.
“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.”
What happens next?
The study was conducted using parasites collected from patients and tested in the laboratory, meaning further research is needed to establish how the mutations affect treatment outcomes in people receiving artemisinin-based combination therapies.
Further to this, understanding how widely the mutations have spread will be important for assessing the potential threat to malaria control programmes elsewhere.
“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.”
For malaria researchers and public health teams, the findings provide both a warning and a potential new surveillance tool. Tracking these mutations could help identify where resistance is emerging and inform efforts to develop the next generation of malaria treatments before current therapies lose their effectiveness.
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