Newly Identified Malaria Mutation Drives Rapid Spread of Lumefantrine Resistance in East Africa
For decades, first-line antimalarial drugs have been the foundation of malaria control across sub-Saharan Africa, but a growing threat is eroding this progress: in recent years, researchers have grown increasingly concerned that malaria parasites are losing sensitivity to standard treatments. Uncovering the genetic origins of this resistance has become an urgent public health priority.
To unpack the drivers of drug-resistant malaria, a team led by Brown University researchers conducted whole-genome analysis on 157 malaria parasite samples sourced from collections gathered across Uganda between 2016 and 2024. The work, published this week in Nature Medicine, points to mutations in a little-studied gene that codes for the protein px1 as the likely cause of rising antimalarial resistance.
“Malaria is still a major killer, particularly across sub-Saharan Africa,” Jeffrey Bailey, an associate professor of pathology at Brown University, said in a press release. “As new forms of drug resistance continue to emerge, we worry it will undo decades of progress controlling malaria spread and lead to far more preventable deaths across the region and beyond.”
When Bailey’s team analyzed the px1 gene in detail, they identified a distinct set of genetic changes: three amino acid mutations paired with two deletions (lost segments of DNA sequence) that are consistently passed down between parasite generations. The team named this mutation cluster PIN.
Normally, genetic recombination each generation gradually breaks down long blocks of genetic sequence over time. However, parasites carrying the PIN mutation passed the entire large genetic region surrounding the mutated px1 to offspring almost entirely intact. This pattern indicates too little time has passed since PIN first emerged for recombination to disrupt the sequence, confirming the mutation has spread extremely rapidly in recent years.
To trace PIN’s origins, the team analyzed historical archived samples and confirmed the mutation was first detected in a 2008 Ugandan sample. Since then, it has spread at an astonishing rate: by 2016, half of all samples from northern Uganda carried PIN; by 2023, the same prevalence was recorded in eastern Uganda. As of 2024, PIN prevalence reached 84% in northern Uganda and 55% in the eastern part of the country.
The team next compared drug responses between parasites with and without the PIN mutation. Experiments confirmed that PIN-carrying parasites had significantly reduced sensitivity to lumefantrine, a core component of artemether-lumefantrine, the first-line combination therapy widely used to treat malaria worldwide. PIN was also linked to reduced sensitivity to other common antimalarial drugs.
To confirm the reduced drug sensitivity was directly caused by px1 mutations rather than other unrelated genetic changes, researchers tested parasites that had been genetically modified to intentionally disrupt the px1 gene, measuring their drug response using the same protocol. They found parasites lacking a functional px1 gene were far more responsive to treatment, confirming px1’s role in resistance.
Separate testing for artemisinin resistance found no significant difference linked to the PIN mutation, which aligns with prior research that ties artemisinin resistance to mutations in the Kelch13 (K13) gene. Before this study, no confirmed genetic marker for lumefantrine resistance existed.
“We didn’t have any validated molecular marker of lumefantrine resistance,” said Karamoko Niare, lead author of the study, in a press release. “We knew that there was a gene involved in partial resistance to artemisinin but couldn’t explain the changes we observed for lumefantrine.” Niare added that the newly identified PIN mutation should be added to routine malaria surveillance systems and studied further to understand its full impact.
When the team analyzed global historical genetic datasets covering samples collected between 2001 and 2015, they found PIN was extremely rare in that period: only five PIN-positive samples were identified in neighboring Democratic Republic of the Congo and Kenya, and no PIN mutations were detected in 13 Ugandan samples collected in 2010 included in the dataset. The full extent of PIN’s spread across national borders remains unclear due to a lack of up-to-date, comprehensive surveillance data.
The study only demonstrates reduced drug susceptibility under laboratory conditions; how much this mutation affects real clinical outcomes for malaria patients remains unconfirmed. Researchers note that to sustain effective malaria treatment globally, it is urgent to build systems that can predict when current drugs will become ineffective, alongside accelerating development of new antimalarial treatments.
This article is adapted from a report originally published by WIRED Japan, translated from Japanese.
