Study finds fast-spreading mutations threatening top malaria drug

Scientists have discovered a set of rapidly spreading genetic mutations in the malaria parasite that reduce its susceptibility to front-line treatments, raising new alarms about the durability of the world's most widely used antimalarial drugs.

New Mutations Threaten Combination Therapy

A team led by researchers at Brown University sequenced the complete genomes of malaria parasites from the blood of hundreds of infected individuals in Uganda and identified a cluster of variants — three mutations and two deletions — associated with decreased susceptibility to artemisinin, lumefantrine, and mefloquine. The findings, published Monday in Nature Medicine, represent the first time a gene mutation has been correlated with reduced susceptibility to multiple drugs used together in artemether-lumefantrine, the most common artemisinin-based combination therapy across sub-Saharan Africa.bioengineer+1

The mutations most strongly implicated are located in or near a gene called PX1, which encodes a phosphoinositide-binding protein. The gene sits close to another parasite gene product previously linked to moderate artemisinin resistance, suggesting the genomic region may harbor interacting pathways that help parasites tolerate drug exposure.brown+1

A Missing Surveillance Tool

"We didn't have any validated molecular marker of lumefantrine resistance," said Karamoko Niaré, the study's first author and an adjunct assistant professor at Brown. "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."brown

The discovery fills a gap in existing genomic surveillance systems, which have relied on markers such as kelch13 variants to monitor artemisinin resistance but lacked tools to explain why parasite populations gradually become less responsive to lumefantrine.bioengineer+1

Urgent Questions Remain

The researchers reported the mutations are spreading rapidly in Uganda, suggesting they confer an evolutionary advantage under drug pressure. How far they have traveled beyond Uganda's borders remains unknown.brown

"It's very concerning that these new mutations are spreading so rapidly — it tells us they are important to the parasite's survival," said Dr. Jeffrey Bailey, an associate professor at Brown and the study's senior author. "As drug resistance continues to emerge, we worry it will undermine control of its spread and result in even more deaths."brown

The CDC has already begun recommending a longer course of artemether-lumefantrine therapy after standard doses failed to cure several travelers returning to the United States. Bailey said the findings underscore the urgency to develop predictive models for when the drug will stop working altogether — and to accelerate the search for new antimalarial compounds.brown