This new drug candidate may finally outsmart tuberculosis

New study in nature highlights the potential of this compound, called CMX410, which targets a key enzyme in the body Mycobacterium tuberculosisThe bacteria that cause tuberculosis. The compound has shown success even against drug-resistant strains, a growing global problem that makes treatment more difficult and less effective.

The research was led by James Sacchettini, Ph.D., president of the Rodger G. Wolfe Welch Science Foundation and professor at Texas A&M University, along with Kees McNamara, Ph.D., senior director of infectious diseases at the Caliber-Skaggs Institute for Innovative Medicines, a division of Scripps Research that develops next-generation therapies.

This discovery arose from a collaboration within the TB Drug Accelerator Program, a Gates Foundation-funded initiative that brings together researchers to develop promising TB treatments.

“A lot of people think that tuberculosis is a disease of the past,” Sacchettini said. “But in reality, this remains a major public health problem that requires significant attention, collaboration and innovation to overcome.”

A new approach to an old enemy

The newly identified compound from AgriLife Research and Calibr-Skaggs works by turning off a vital enzyme, polyketide synthase 13 (Pks13), which bacteria need to build their protective cell wall. Without this structure M. Tuberculosis The body cannot survive or be injured.

Scientists have long known that Pks13 is an important target for TB drugs, but developing a safe and effective inhibitor has proven difficult. The CMX410 succeeds where previous attempts have failed. Its design makes it very specific to its target, resulting in fewer unwanted effects. The compound forms an irreversible bond with a critical site on Pks13, preventing resistance from developing and keeping the drug focused on its intended target.

To achieve this, the researchers used a technique known as click chemistry, a method that links molecules together like puzzle pieces. This approach was pioneered by co-author Barry Sharpless, Ph.D., the W. M. Keck Professor of Chemistry at Scripps Research Institute and a two-time Nobel laureate. His work has opened the door to vast libraries of chemical compounds that can be rapidly tested and improved.

“This technology represents a new tool for drug design,” McNamara said. “We expect to see its uses expand in the coming years to help address critically needed public health concerns, including tuberculosis.”

Early results are promising

The team began by screening a group of compounds from Sharpless’s laboratory to find those capable of slowing down M. Tuberculosis growth. After months of optimization, led by co-first authors Baiyuan Yang, PhD, and Paridhi Sukhija, PhD, CMX410 emerged as the most effective and balanced candidate.

Yang’s team tested more than 300 different species to fine-tune the compound’s strength, safety, and selectivity. The final version was tested against 66 different strains of TB, including multidrug-resistant samples from patients, and proved effective in almost all cases.

“Identifying this new target was an exciting moment,” said Sukhija, who led several early studies that showed CMX410 could target a previously unexplored gene. “It opened a whole new path forward, especially against strains that have learned to evade existing treatments.”

The researchers also found that CMX410 can be safely used alongside existing TB medications, an important advantage given that treatment typically involves taking multiple medications for several months. In animal experiments, no negative side effects were observed even at the highest doses. Because of its specificity, the compound is unlikely to disturb healthy bacteria or cause gut dysfunction — a problem often associated with traditional antibiotics.

Getting closer to better treatments

The addition of a specialized chemical group that allows CMX410 to permanently attach to its target makes it one of the most selective compounds of its kind. Although more studies are needed before it can be tested in humans, early results indicate strong potential for treating tuberculosis in the future.

“These early results are very encouraging,” said Ina Krieger, Ph.D., a senior research scientist in Sacchettini’s lab and co-first author on the paper. “Antibiotics that target the cell wall have long been a cornerstone of tuberculosis treatment. However, after decades of widespread use, their effectiveness is diminished by the emergence of drug-resistant strains.

“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. Through these efforts, we hope to help bring the world closer to a TB-free future.”