A new study in Nature highlights the potential of this compound, called CMX410, which targets a key enzyme in Mycobacterium tuberculosis, the bacterium that causes 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., the Rodger J. Wolfe-Welch Foundation Chair in Science and professor at Texas A&M University, along with Case McNamara, Ph.D., senior director of infectious disease at the Calibr-Skaggs Institute for Innovative Medicines, a division of Scripps Research that develops next-generation therapies.

This discovery emerged from collaborations within the TB Drug Accelerator program, a Gates Foundation-funded initiative that brings together researchers to advance the most promising tuberculosis treatments.

"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."

A new approach to an old enemy

The newly identified compound from AgriLife Research and Calibr-Skaggs works by shutting down a vital enzyme, polyketide synthase 13 (Pks13), which the bacterium needs to build its protective cell wall. Without this structure, M. tuberculosis cannot survive or infect the body.

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

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

"This technique represents a new tool for drug design," said McNamara. "We expect to see its uses expand in the coming years to help address public health concerns with a critical need, including tuberculosis."

Promising early results

The team began by screening a collection of compounds from the Sharpless lab to find those capable of slowing M. tuberculosis growth. After months of optimization, led by co-first authors Baiyuan Yang, Ph.D., and Paridhi Sukheja, Ph.D., CMX410 emerged as the most effective and balanced candidate.

Yang's team tested more than 300 variations to fine-tune the compound's power, safety, and selectivity. The final version was tested against 66 different TB strains, including multidrug-resistant samples taken from patients, and proved effective in nearly all cases.

"Identifying this novel target was an exciting moment," said Sukheja, who led many early studies showing CMX410 could target a previously unexplored gene. "It opened up a completely new path forward, especially against strains that have learned to evade existing treatments."

The researchers also found that CMX410 can be used safely alongside existing TB drugs, a crucial advantage since treatment typically involves multiple medications taken for several months. In animal testing, no negative side effects were observed even at the highest doses. Because of its precision, the compound is unlikely to disturb healthy bacteria or cause gut imbalance -- an issue often linked to traditional antibiotics.

Moving closer to better therapies

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 findings suggest strong potential for future TB treatment.

"These early results are very encouraging," said Inna Krieger, Ph.D., senior research scientist in Sacchettini's lab and co-first author of the paper. "Cell wall-targeting antibiotics have long been a cornerstone of tuberculosis treatment. However, after decades of widespread use, their effectiveness is waning due to the rise 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 move the world closer to a future free from tuberculosis."

On average, people who walked between 3,000 and 5,000 steps a day experienced about three years of delay in cognitive decline. Those who walked 5,000 to 7,500 steps per day saw that delay extend to around seven years. In contrast, participants who were largely inactive showed faster accumulation of tau proteins in the brain, which is associated with Alzheimer's progression, and more rapid declines in thinking skills and daily functioning.

"This sheds light on why some people who appear to be on an Alzheimer's disease trajectory don't decline as quickly as others," said senior author Jasmeer Chhatwal, MD, PhD, of the Mass General Brigham Department of Neurology. "Lifestyle factors appear to impact the earliest stages of Alzheimer's disease, suggesting that lifestyle changes may slow the emergence of cognitive symptoms if we act early."

Long-Term Study on Activity and Brain Changes

Researchers examined 296 individuals aged 50 to 90 who showed no cognitive impairment at the start of the Harvard Aging Brain Study. Participants wore waistband pedometers to track physical activity and underwent PET scans to measure amyloid-beta plaques and tau tangles in the brain. They completed yearly cognitive assessments over a period ranging from two to 14 years (average = 9.3 years), and a subset received additional brain scans to monitor changes in tau over time.

The results showed that participants with elevated amyloid-beta who took more daily steps experienced slower cognitive decline and a slower buildup of tau proteins. Statistical modeling indicated that the primary benefit of physical activity came from its association with slower tau accumulation. Among participants with low amyloid-beta levels, there was little evidence of either cognitive decline or tau buildup, and no significant link to activity levels.

Building Cognitive Resilience Through Movement

"We are thrilled that data from the Harvard Aging Brain Study has helped the field better understand the importance of physical activity for maintaining brain health," said co-author Reisa Sperling, MD, a neurologist at Mass General Brigham and co-principal investigator of the Harvard Aging Brain Study. "These findings show us that it's possible to build cognitive resilience and resistance to tau pathology in the setting of preclinical Alzheimer's disease. This is particularly encouraging for our quest to ultimately prevent Alzheimer's disease dementia, as well as to decrease dementia due to multiple contributing factors."

The team plans to further explore which types of physical activity are most beneficial, including how intensity and long-term exercise patterns might influence brain health. They also aim to uncover the biological mechanisms that connect physical activity, tau buildup, and cognitive function. The researchers believe these insights could inform future clinical trials that test whether exercise-based interventions can slow cognitive decline in older adults, particularly those at elevated risk for Alzheimer's.

Empowering People to Take Action

"We want to empower people to protect their brain and cognitive health by keeping physically active," said first-author Wai-Ying Wendy Yau, MD, a cognitive neurologist at Mass General Brigham. "Every step counts -- and even small increases in daily activities can build over time to create sustained changes in habit and health."

Authorship: In addition to Yau, Chhatwal and Sperling, Mass General Brigham authors include Dylan R. Kirn, Michael J. Properzi, Aaron P. Schultz, Zahra Shirzadi, Kailee Palmgren, Paola Matos, Courtney Maa, Stephanie A. Schultz, Rachel F. Buckley, Dorene M. Rentz, and Keith A. Johnson. Additional authors include Jennifer S. Rabin and Jeremy J. Pruzin.

Disclosures: The authors have no competing interests relevant to the current study. Potential conflicts of interest outside of the submitted work are listed in Nature Medicine.

Funding: This work was supported by the National Institutes of Health (K23 AG084868, K01 AG084816, P01 AG036694, K24 AG035007, R01 AG062667, R01 AG071865, P41EB015896, S10RR021110, S10RR023401, S10RR023043), the Doris Duke Charitable Foundation Clinical Scientist Development Award, and the Massachusetts Life Sciences Center.