New study shows promise for better TB treatments, La Jolla researchers say

One of the deadliest infectious diseases can be difficult to treat because of drug-resistant strains. But with a new study, scientists from a group of institutions including Scripps Research in La Jolla say they are seeing a promising new treatment option emerge for tuberculosis.

The study, led by Texas A&M University’s Department of Biochemistry and Biophysics and Scripps Research’s Calibr-Skaggs Institute for Innovative Medicines, was released July 30 in the scientific journal Nature.

More than 40 authors are listed on the paper, including scientists from Weill Cornell Medicine, Rutgers University, Colorado State University and Shanghai Jiao Tong University’s Institute of Translational Medicine.

Central to the group’s discoveries is the development of a new compound called CMX410.

“The drug uniquely targets a crucial enzyme in Mycobacterium tuberculosis, the bacterium responsible for tuberculosis,” according to a statement from Scripps.

With the compound blocking the key enzyme polyketide synthase 13 (Pks13), M. tuberculosis is unable to build a protective cell wall. As a result, it is unable to survive long enough to sustain an infection.

Tuberculosis generally affects the lungs but also can affect other parts of the body. Typical symptoms include a chronic cough with mucus containing blood, plus fever, night sweats and weight loss.

The study determined that CMX410 was effective against otherwise drug-resistant infections in mice. Also, there were no adverse effects observed in a rat toxicity study, the researchers said.

With these results, scientists said, the discoveries surrounding TB treatment could help address other critical public health concerns.

Case McNamara, senior director of infectious disease at the Calibr-Skaggs Institute and co-senior author of the study, described the findings as a breakthrough and explained them with the analogy of a lock and key.

“You can imagine the lock being the drug target and the key being the very specific inhibitor that is able to fit into that lock,” McNamara said.

“The cool thing about the covalent inhibitor is that it’s the equivalent of putting Super Glue all over that key. So now when you insert that key into its lock and you try to pull out, it’s glued in there.”

The study has been in the works since about 2018. The scientific groups came together through the TB Drug Accelerator program, an effort launched by the Gates Foundation to conduct research to design “high-impact drug candidates.”

Groups in TBDA work together by sharing their compound libraries and data, as well as animal studies.

The new study also draws on the work of co-author Barry Sharpless, a professor of chemistry at Scripps Research who coined “click chemistry,” a method in which molecules are snapped together in a fashion similar to assembling puzzle pieces.

The Calibr-Skaggs Institute is the nonprofit drug development division of Scripps Research.

“We’re technically underneath the same umbrella,” said McNamara of Calibr-Skaggs. “So what’s really neat is that Barry Sharpless, who’s a two-time Nobel laureate, works right across the street.”

McNamara also thanked Peter Schultz, president and chief executive of Scripps Research and founding director of Calibr-Skaggs, for creating “a hybrid design between industry and academics.”

“This is a perfect case where collaboration is not being oversold in any way,” McNamara said. “This started as a collaboration of taking a really interesting chemistry approach and applying that as a drug discovery approach to tuberculosis.

“On top of that, we now bring in the group from Texas A&M … and they complement what we do perfectly. We do drug discovery really, really well and they do structural biology and biochemical and they’re very good at … looking at things from the atomic resolution side.”