A Mutation Is Making It Easier for Drug-Resistant Malaria to Spread

The main drug that has been in use for decades to combat malaria in sub-Saharan Africa is running into a problem: In recent years, researchers have become increasingly concerned that parasites are becoming less sensitive to treatment. Identifying the underlying genetic factors has become an urgent priority.

In an attempt to identify the reason for drug-resistant malaria, a team led by Brown University researchers conducted whole-genome analysis of 157 malaria parasite samples selected from specimens collected in Uganda between 2016 and 2024. The work, published in Nature Medicine this week, shows evidence that mutations in a gene that encodes a protein called px1, which had previously received little attention, is likely responsible for the rise in drug resistance.

“Malaria still is a major killer, particularly in sub-Saharan Africa,” Jeffrey Bailey, an associate professor at Brown University specializing in pathology, says in a press release . “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.”

When Bailey’s research team examined the px1 gene in detail, they found that a set consisting of three amino acid mutations and two deletions—the loss of a portion of a chromosome or DNA sequence—was being passed down through generations. The researchers named this cluster of mutations PIN.

Genes undergo recombination with each generation, causing their sequences to gradually break down. However, malaria parasites carrying the PIN mutation were found to have passed on a large region surrounding the px1 gene to multiple individuals almost entirely intact. This suggests that not enough time has elapsed since the PIN mutation emerged for genetic recombination to occur, indicating that it has spread rapidly in recent years.

To pinpoint when the PIN mutation first appeared, the research team examined historical samples and confirmed the presence of the PIN mutation for the first time in a sample from 2008. Since then, the PIN mutation has spread at an astonishing rate. By 2016, half of the samples from northern Uganda showed evidence of the mutation, and as of 2023, the same was true for eastern Uganda. By 2024, the prevalence had reached 84 percent in the north and 55 percent in the east.

Furthermore, the research team compared the response to common antimalarial drugs between malaria parasites carrying the PIN mutation and those that did not. The results of the experiment showed that malaria parasites carrying the PIN mutation exhibited reduced sensitivity to lumefantrine—one component of the combination drug artemether-lumefantrine that’s commonly used to treat the parasite—as well as other antimalarials.