Scientists have developed a promising compound called CMX410 that inhibits a key enzyme in the tuberculosis bacterium, showing effectiveness against drug-resistant strains. The discovery, published in Nature, emerges from collaborative research funded by the Gates Foundation. Early tests suggest it could enable shorter, safer treatments for the world's deadliest infectious disease.
Tuberculosis remains a major global health threat, killing more people than any other infectious disease despite available treatments. A new study in Nature introduces CMX410, a compound designed to target polyketide synthase 13 (Pks13), an enzyme essential for the Mycobacterium tuberculosis bacterium's cell wall construction. By forming an irreversible bond with Pks13, CMX410 disrupts this process, preventing bacterial survival and infection without promoting resistance.
The research was led by James Sacchettini, Ph.D., professor at Texas A&M University, and Case McNamara, Ph.D., senior director at the Calibr-Skaggs Institute for Innovative Medicines, part of Scripps Research. It stems from the TB Drug Accelerator program, a Gates Foundation initiative uniting experts to develop advanced tuberculosis therapies. "A lot of people think of tuberculosis as a disease of the past," Sacchettini said. "But in reality, it remains a major public health issue requiring significant attention, collaboration and innovation to overcome."
Researchers employed click chemistry, pioneered by co-author Barry Sharpless, Ph.D., a two-time Nobel Laureate at Scripps Research, to create and screen compound libraries. After testing over 300 variations, co-first authors Baiyuan Yang, Ph.D., and Paridhi Sukheja, Ph.D., optimized CMX410 for potency, safety, and selectivity. It proved effective against 66 tuberculosis strains, including multidrug-resistant ones from patients.
"Identifying this novel target was an exciting moment," Sukheja said. "It opened up a completely new path forward, especially against strains that have learned to evade existing treatments." Animal studies showed no side effects at high doses, and CMX410 works safely with current drugs, potentially shortening the months-long regimens that often lead to poor adherence.
Inna Krieger, Ph.D., senior research scientist in Sacchettini's lab and co-first author, noted the compound's precision avoids disrupting healthy bacteria. "These early results are very encouraging," she said. "We are working to discover new drugs that disrupt essential biological processes and identify optimal combinations with existing drugs to enable shorter, safer and more effective treatment regimens." While human trials are needed, CMX410 represents a targeted advance against rising drug resistance.