Newswise — June 29, 2021 – Nutley, NJ – Scientists from the Hackensack Meridian Center for Discovery and Innovation, working with collaborators from across the globe, uncovered the mechanism of action of a novel anti-tuberculosis drug that they have helped develop.

The new findings show how the enzyme inhibitor triaza-coumarin, or TA-C, is metabolized by the TB germs, which makes it effective in inhibiting the disease from within, like in a “Trojan horse” attack, according to the new paper in the journal Proceedings of the National Academy of Sciences.*

“This is a promising new direction of research,” said Thomas Dick, member of the CDI faculty. “We are hoping this work can make a difference in the ongoing fight against TB.”

“The scientists at the CDI who specialize in tuberculosis and other mycobacteria are at the vanguard of their specialty,” said David Perlin, PhD., the chief scientific officer and senior vice president of the CDI.  “Their promising new lines of research offer hope against a scourge that continues to kill in huge numbers, year after year."  

Bacterial metabolism can cause intrinsic drug resistance – but it can also convert inactive parent drugs to bioactive derivatives, as is the case for several antimycobacterial “prodrugs.” These “prodrugs” are biologically inactive compounds which are broken down by the bacteria to create the effective byproduct compounds within the bacterial cell.

The scientists show in the paper that intra-bacterial metabolism of TA-C, a new Mycobacterium tuberculosis dihydrofolate reductase (DHFR) inhibitor with moderate affinity for its target, boosts its on-target activity by two orders of magnitude. The TB germ takes up and metabolizes the TA-C – but the byproducts inhibit its function from within. 

This is the first ‘prodrug-like’ antimycobacterial that possesses baseline activity in the absence of intracellular bio-activation. By describing how it works in this latest paper, the authors have provided the foundational basis of a novel class of DHFR inhibitors and uncovered a new antibacterial drug discovery concept. 

This new methodology could be crucial in the ongoing fight against TB, which kills 1.3 million people across the globe annually, and which disproportionately afflicts the developing world. New drugs are desperately needed to fight drug-resistant strains of the disease. 

The CDI team included Dr. Wassihun Wedajo Aragaw in the Dick lab who uncovered the mechanism of action, as well as colleagues Drs. Veronique Dartois, Martin Gengenbacher and Matthew D. Zimmerman. The international team who collaborated with the CDI included Brendon Lee and Colin Jackson from the Australian National University, and Xuan Yang and Wai-Keung Chui of the National University of Singapore. 

Dick and Chui first published a paper in 2017 describing the TA-C compound’s apparent effectiveness against TB bacteria.

 

* Wassihun Wedajo Aragaw, Brendon M. Lee, Xuan Yang, Matthew D. Zimmerman, Martin Gengenbacher, Véronique Dartois, Wai-Keung Chui, Colin J. Jackson, Thomas Dick (2021) Potency boost of a Mycobacterium tuberculosis dihydrofolate reductase inhibitor by multi-enzyme F420H2 dependent reduction.

 

ABOUT HACKENSACK MERIDIAN HEALTH

Hackensack Meridian Health is a leading not-for-profit health care organization that is the largest, most comprehensive and truly integrated health care network in New Jersey, offering a complete range of medical services, innovative research and life-enhancing care.

Hackensack Meridian Health comprises 17 hospitals from Bergen to Ocean counties, which includes three academic medical centers – Hackensack University Medical Center in Hackensack, Jersey Shore University Medical Center in Neptune, JFK Medical Center in Edison; two children’s hospitals - Joseph M. Sanzari Children’s Hospital in Hackensack, K. Hovnanian Children’s Hospital in Neptune; nine community hospitals – Bayshore Medical Center in Holmdel, Mountainside Medical Center in Montclair, Ocean Medical Center in Brick, Palisades Medical Center in North Bergen, Pascack Valley Medical Center in Westwood, Raritan Bay Medical Center in Old Bridge, Raritan Bay Medical Center in Perth Amboy, Riverview Medical Center in Red Bank, and Southern Ocean Medical Center in Manahawkin; a behavioral health hospital – Carrier Clinic in Belle Mead; and two rehabilitation hospitals - JFK Johnson Rehabilitation Institute in Edison and Shore Rehabilitation Institute in Brick.

Additionally, the network has more than 500 patient care locations throughout the state which include ambulatory care centers, surgery centers, home health services, long-term care and assisted living communities, ambulance services, lifesaving air medical transportation, fitness and wellness centers, rehabilitation centers, urgent care centers and physician practice locations. Hackensack Meridian Health has more than 36,000 team members, and 7,000 physicians and is a distinguished leader in health care philanthropy, committed to the health and well-being of the communities it serves.

The network’s notable distinctions include having four of its hospitals are among the top hospitals in New Jersey for 2020-21, according to U.S. News & World Report. Additionally, the health system has more top-ranked hospitals than any system in New Jersey. Children’s Health is again ranked a top provider of pediatric health care in the United States and earned top 50 rankings in the annual U.S. News’ 2020-21 Best Children’s Hospitals report.   Other honors include consistently achieving Magnet® recognition for nursing excellence from the American Nurses Credentialing Center and being named to Becker’s Healthcare’s “150 Top Places to Work in Healthcare/2019” list.

The Hackensack Meridian School of Medicine, the first private medical school in New Jersey in more than 50 years, welcomed its first class of students in 2018 to its campus in Nutley and Clifton. The Hackensack Meridian Center for Discovery and Innovation (CDI), housed in a fully renovated state-of-the-art facility, seeks to translate current innovations in science to improve clinical outcomes for patients with cancer, infectious diseases and other life-threatening and disabling conditions.

Additionally, the network partnered with Memorial Sloan Kettering Cancer Center to find more cures for cancer faster while ensuring that patients have access to the highest quality, most individualized cancer care when and where they need it.

Hackensack Meridian Health is a member of AllSpire Health Partners, an interstate consortium of leading health systems, to focus on the sharing of best practices in clinical care and achieving efficiencies.

 

To learn more, visit www.hackensackmeridianhealth.org.

 

About the Center for Discovery and Innovation

The Center for Discovery and Innovation, a newly established member of Hackensack Meridian Health, seeks to translate current innovations in science to improve clinical outcomes for patients with cancer, infectious diseases and other life-threatening and disabling conditions. The CDI, housed in a fully renovated state-of-the-art facility, offers world-class researchers a support infrastructure and culture of discovery that promotes science innovation and rapid translation to the clinic.

For additional information, please visit www.hmh-cdi.org.