Team Science Leads to Antimalarial Drug Discovery

Researchers have discovered a new chemical compound, MED6-189, that is a strong inhibitor of parasites that are resistant to commonly used antimalarial drugs. The high potency, excellent therapeutic profile, and unique mode of action of MED6-189 make it an excellent addition to the antimalarial drug pipeline, the researchers said.

The study, funded by the National Institutes of Health, was published in Science.

Despite developments in preventing and treating malaria, the disease remains a leading public health threat worldwide. In 2022, the disease caused an estimated 247 million clinical cases and 619,000 deaths, according to the World Health Organization’s World Malaria Report 2023.

One of the biggest challenges in controlling malaria is the resistance of the parasite to commonly used antimalarial drugs, said Choukri Ben Mamoun, PhD, professor of medicine (infectious diseases), microbial pathogenesis, and pathology at Yale School of Medicine (YSM) and corresponding author of the study.

With the aim of developing a new drug that is easy to produce, effective, and potent against both drug-sensitive and drug-resistant strains of malaria, researchers from academic labs at YSM, the University of California, Irvine, and the University of California, Riverside, utilized a multidisciplinary approach to understand how MED6-189, a structural analogue of a marine sponge secondary metabolite, works.

“This study represents a true systems biology approach to antimalarial drug discovery and is an excellent example of a collaborative team-science effort incorporating expertise across multiple institutions and disciplines,” said Amy Bei, PhD, associate professor of epidemiology (microbial diseases) at the Yale School of Public Health and co-author of the study.

The researchers discovered that in Plasmodium falciparum, the pathogen responsible for the most severe form of human malaria, MED6-189 could inhibit both the parasite’s asexual development in the blood and its ability to undergo sexual differentiation, a critical step in malaria transmission.

Because MED6-189 targets multiple processes, the probability of the parasite developing resistance against it is low. “To render the compound ineffective, the parasite would need to alter multiple genes and metabolic functions, making resistance much less likely,” Ben Mamoun said.

This unique ability of MED6-189 could also reduce the need for additional drugs, thereby lowering the potential for increased toxicity, he said.

Both Bei and Ben Mamoun stress the urgent need to continue optimizing this class of compounds and identifying novel antimalarials.

“In the context of emerging partial resistance to artemisinin-based combination therapies globally, and alarmingly in Africa, which bears the greatest burden of the disease, identifying and validating promising new antimalarial leads requires an all-hands-on-deck collaborative approach to tackle this critical challenge,” Bei said.

“Malaria is here to stay, and with widespread resistance, we need to join efforts to develop better therapeutic strategies,” Ben Mamoun said. “This compound could function on its own like a combination therapy, which typically uses multiple drugs to target a single organism and lower the chance of resistance, much like we do with HIV and other diseases.”

Other authors of the paper include Zeinab Chahine, Steven Abel, Thomas Hollin, Griffin Lee Barnes, Jonathan Chung, Mary Elizabeth Daub, Isaline Renard, Jae Yeon Choi, Pratap Vydyam, Anasuya Pal, Magdalena Alba-Argomaniz, Charles Banks, Jay Kirkwood, Anita Saraf, Isabel Camino, Pablo Castaneda, Maria Cuevas, Jaime De Mercado-Arnanz, Elena Fernandez-Alvaro, Adolfo Garcia-Perez, Nuria Ibarz, Sara Viera-Morilla, Jacques Prudhomme, Chester Joyner, Laurence Florens, Christopher Vanderwal, and Karine Le Roch.

Yale School of Medicine’s Department of Internal Medicine Section of Infectious Diseases engages in comprehensive and innovative patient care, research, and educational activities for a broad range of infectious diseases. Learn more at Infectious Diseases.