Gene Mutation Found to Be Accelerating Spread of Drug-Resistant Malaria
Brown University researchers have identified a cluster of mutations in the px1 gene that reduces malaria parasites' sensitivity to a widely used antimalarial drug and has spread rapidly across Uganda in recent years. The discovery could help build better surveillance and treatment strategies.
A team led by Brown University researchers has identified a likely genetic cause behind the declining effectiveness of a decades-old antimalarial drug in sub-Saharan Africa. The study, published this week in Nature Medicine, analyzed whole genomes from 157 malaria parasite samples collected in Uganda between 2016 and 2024.
The researchers found that a previously overlooked gene encoding a protein called px1 carries a cluster of mutations — three amino acid changes and two DNA deletions — which they named PIN. Genetic analysis showed that a large stretch of DNA surrounding the px1 gene had been passed down nearly intact across generations of parasites, a sign that the mutation is relatively recent and has spread unusually fast, since normal genetic recombination hadn't yet had time to break the sequence apart.
Tracing historical samples, the team found the earliest evidence of the PIN mutation in a sample from 2008. Its spread since then has been dramatic: by 2016, half of the samples from northern Uganda carried it, and by 2023 the same was true in eastern Uganda. By 2024, prevalence had climbed to 84 percent in the north and 55 percent in the east.
Parasites carrying the PIN mutation showed reduced sensitivity to lumefantrine — a component of the widely used combination drug artemether-lumefantrine — as well as to other antimalarials. Comparing these results with parasites in which the px1 gene had been deliberately disrupted in an earlier study confirmed that the gene itself drives the reduced drug response. Notably, no clear effect was found on resistance to artemisinin, malaria's other key treatment component.
Previous research had linked artemisinin resistance to mutations in a gene called Kelch13, but no validated genetic marker existed for lumefantrine resistance until now. The study's lead author said the mutation should be added to disease surveillance systems and studied further.
Looking at global genetic databases from 2001 to 2015, the team found the PIN mutation was still extremely rare then, appearing in only five samples from the Democratic Republic of the Congo and Kenya, and absent from 13 Ugandan samples collected in 2010. How far the mutation has since spread across borders remains unclear due to limited up-to-date data. The researchers stressed the urgent need for systems that can predict when drugs will stop working, alongside development of new treatments.
