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.
To confirm whether these results were truly due to the px1 gene itself, the researchers used malaria parasites created in a previous study by intentionally disrupting the px1 gene and examined their response to the drugs in the same manner. They found that the parasites lacking the px1 gene responded more strongly to these treatments. In a separate test examining resistance to artemisinin, no clear differences were observed due to the PIN mutation.
Previous research has pointed to mutations in a gene called Kelch13 (K13) being associated with artemisinin resistance. However, for lumefantrine, no verified marker mutations had been identified.
“We didn’t have any validated molecular marker of lumefantrine resistance,” Karamoko Niare, the paper’s lead author, says in a press release. “We knew that there was a gene involved in partial resistance to artemisinin but couldn’t explain changes observed for lumefantrine.” He noted that this new mutation should be incorporated into surveillance systems and further studied.
When the research team examined historical global genetic databases collected between 2001 and 2015, it found that the PIN mutation was still extremely rare at that time, with only five samples identified in the neighboring countries of the Democratic Republic of the Congo and Kenya. Notably, the mutation was not detected in 13 samples from Uganda collected in 2010 that were included in this dataset. The extent to which this mutation has spread across borders remains unclear due to a lack of up-to-date data.
This study merely demonstrated changes in drug susceptibility at the laboratory level; the extent to which this affects clinical outcomes in actual malaria patients remains unclear. The researchers point out that, in order to continue providing effective malaria treatment, it is urgent to establish systems for predicting when drugs will become ineffective and to develop new treatments.
This story originally appeared on WIRED Japan and has been translated from Japanese.
