By Joke Kujenya
HUMANITY’s AGE-long battle with malaria may soon turn a corner, thanks to a groundbreaking scientific discovery.
For decades, the mosquito-borne disease has haunted tropical regions, claiming hundreds of thousands of lives each year, most of them children under five.
But as the malaria parasite grows increasingly resistant to existing drugs, scientists reveal they have now uncovered fresh insights that could transform the way the disease is treated.
Now, researchers at Columbia and Drexel universities said they have unveiled a breakthrough: the first high-resolution three-dimensional map of a malaria parasite’s vital sodium pump, known as PfATP4, and the discovery of a binding partner essential to its function.
The finding offers hope for designing medications that resist parasite escape.
Drug resistance has dogged malaria control for decades. The parasite Plasmodium falciparum has repeatedly evolved insensitivity to key antimalarial agents, undermining progress.
Scientists also noted that they have eyed PfATP4 as one of the parasite’s Achilles’ heels: blocking that pump disrupts its delicate sodium balance, killing it.
But past attempts to design PfATP4 inhibitors stumbled when parasites quickly mutated, they noted.
The new study, published 20 October 2025 in Nature Communications, addresses that challenge directly by providing previously missing detail: researchers mapped PfATP4 in its native parasite environment, revealing not only the pump’s structure but also a companion protein that stabilises it.
(Endogenous structure of antimalarial target PfATP4 reveals an apicomplexan-specific P-1 type ATPase modulator) Columbia Irving Medical Center+3Nature+3PubMed+3
The structural breakthrough also rests on a clever technical innovation.
Earlier studies according to the report often tried to produce parasite proteins in surrogate systems such as yeast or bacteria. But PfATP4, a complex membrane protein, often misfolds or lacks proper interactions when removed from its natural context.
That limitation has long hindered efforts to see exactly where drugs bind and where resistance arises. Columbia Irving Medical Center+2Nature+2
Co-senior author Chi-Min Ho, assistant professor at Columbia’s Vagelos College, has pioneered methods to isolate proteins directly from parasite-infected red blood cells.
That endogenous approach allowed the team to visualise PfATP4 with cryo-electron microscopy in its native configuration.
“Every year, malaria parasites adapt to outsmart our medicines,” Ho says.
“With the structure of PfATP4 now in hand and the discovery of this unknown partner, we have identified vulnerabilities that can be exploited for new therapies.” Columbia Irving Medical Center+1
Mapping the pump in this way enabled the team to overlay known resistance mutations—such as G358S, one of the more notorious ones—directly onto the 3D model., he noted
They observed that several resistance mutations cluster around the pump’s ion-binding region, showcasing how small structural shifts may allow mutation to disable drug binding without fatally disabling the pump itself. Nature+2PubMed+2
But the surprise came in the form of a heretofore unknown protein bound to PfATP4.
The researchers said they named it PfATP4 Binding Protein (PfABP).
It appears to cling on and stabilise PfATP4’s structure, essentially serving as a chaperone or regulator.
In lab experiments, when PfABP was suppressed or knocked down, PfATP4 levels collapsed and the parasites died, indicating that the partnership is essential to parasite survival. Drexel University+2Columbia Irving Medical Center+2
The human-interest angle is profound as the scientists said they now have a fresh target for drug design that may be less mutable, thereby harder for the parasite to evade through mutation.
Because PfABP is relatively conserved (less prone to change) and unique to malaria parasites, medicines aimed at disrupting the PfATP4–PfABP interaction could remain effective longer.malariaworld.org+4Drexel University+4Columbia Irving Medical Center+4.
In the past, experimental compounds like cipargamin have targeted PfATP4 directly, but even those have been thwarted by the parasite’s ability to evolve.
The new structural map suggests fresh binding pockets, regulatory sites and angles of attack that may circumvent known resistance paths.
“The findings provide a blueprint for next-generation drug discovery, offering ways to design molecules that target PfATP4,” says Akhil Vaidya, co-senior author at Drexel’s College of Medicine. Columbia Irving Medical Center+1
Vaidya said as the world grapples with rising drug resistance, the timing of this discovery is critical.
Up till now, malaria kills more than 600,000 people annually and any stagnation in control efforts could reverse hard-won gains. Drexel University+2Columbia Irving Medical Center+2, Vaidya stressed.
Translating this discovery into medicine will require years of chemistry, validation, safety trials and large-scale field testing against diverse parasite populations, Vaidya still stressed.
Yet, many researchers consider this work a pivot point where parasite biology reveals its own weak spots.
By turning the parasite’s internal machinery against itself, scientists may design drugs capable of outlasting the parasite’s capacity to adapt, the scientists note.
They described this breakthrough as an essential truth of modern biomedical science: for high-value targets like PfATP4, the path forward lies not in brute drug screening but in deep structural understanding.
Scientists also stressed that with both the pump and its crucial companion now in view, the fight against malaria may gain vital ground.
