Every year, over 600,000 people die of malaria – especially children, and especially in Africa. Most drugs work by interrupting the metabolism of the parasite while it is in the host’s bloodstream, and are largely effective, saving millions of lives. But they do not prevent transmission or target every stage of the malaria life-cycle, and they are also susceptible to resistance as parasites evolve into new strains. In certain parts of Southeast Asia and Africa, drug-resistant malaria strains are already a reality.

For this reason, scientists such as James Spudich, co-founder of Kainomyx, a California-based biotech company , Anne Houdusse (Instiut Curie, France) and Kathleen Trybus (University of Vermont, US) , have been exploring the possibility of a new type of malaria drug – one that tackles the motility of the parasite, rather than its metabolism. Back in 2023, their collaboration led to the identification of the first-in-class inhibitor, KNX-002, that could target the molecular motor myosin A of Plasmodium falciparum (PfMyoA)– the parasite behind the most deadly form of human malaria. ID30B crystallography by Dihia Moussaoui, an ESRF postdoctoral researcher, and Christoph Müller-Dieckmann, the beamline scientist-in-charge, revealed how the drug worked.

That structural insight didn't just explain KNX-002 mechanism of action , it helped Kainomyx to create a potentially better inhibitor. Biochemical assays show that its successor, KNX-115, is more than 20 times more potent at inhibiting myosin A. Now Moussaoui and Müller-Dieckmann have gone back to the ID30B beamline, this time solving the structure of KNX-115 bound to PfMyoA at high atomic resolution — to reveal exactly what makes it so much more effective.

“Thanks to the ESRF–EBS upgrade, ID30B benefits from a higher brilliance, lower emittance beam, delivering a smaller, more coherent X-ray spot with substantially increased flux density at the sample,” says Moussaoui. “This allowed us to use shorter exposure times per frame while still collecting sufficient signal, directly reducing the radiation dose absorbed by each crystal over the course of data collection. It also allowed us to collect high-quality data from crystal volumes that would have been difficult to exploit with a less brilliant source.”

Normally, myosin A repeatedly changes shape as it grabs onto actin filaments. The ESRF data show that KNX-115 wedges into a pocket by the motor’s active site, preventing shape changes and leaving the parasite unable to move or infect new human cells. “The results provide a framework for the rational design of the next generation of myosin A inhibitors, and further strengthen the potential of this unconventional motor as a therapeutic target,” says Moussaoui.

There's more good news: separate lab tests indicate that parasites may find it relatively difficult to evolve resistance to KNX-115. Darshan Trivedi (a Kainomyx co-founder ) and colleagues deliberately evolved malaria parasites while treating them with the new inhibitor, and found that the resulting mutants exhibited only weak resistance.

The malaria parasite belongs to a much larger family of parasites that all rely on this same molecular motor to move. That family includes Toxoplasma (which causes toxoplasmosis, a serious risk for people with weakened immune systems) and Cryptosporidium (a leading cause of diarrheal disease worldwide). The in vitro studies showed that KNX-115 also blocked the growth of these parasites, as well as Eimeria, which affects livestock and poultry. That means this single drug candidate could one day help fight not just malaria, but a whole family of related diseases, in people and in animals alike.

Moussaoui is working on the analysis of ID30B data of another malarial myosin motor, which initiates the parasite’s invasion. “It could represent another interesting target for a drug, in a combination-therapy approach,” she says.

Reference:

Trivedi, Darshan V. et al. Antimalarial cytoskeletal targeting with broad apicomplexan activity. PNAS 123, e2608709123 (2026) https://doi.org/10.1073/pnas.2608709123

Text by Jon Cartwright