June 29, 2021, Nutley (NJ) - Scientists at Hackensack Meridian Center for Discovery and Innovation discovered the mechanism of an anti-tuberculosis medication that they helped to develop.According to the latest paper published in Proceedings of the National Academy of Sciences, the findings reveal how the enzyme inhibitor triazacoumarin (or TA-C) is metabolized in TB germs. This makes it more effective in stopping the disease from within like in a trojan horse attack.Thomas Dick, a member of the CDI faculty, said that "this is a promising new area of research." "We hope this work will make a difference in our ongoing fight against TB."David Perlin (PhD.), chief scientist and senior vice president at the CDI, stated that scientists at the CDI who are experts in tuberculosis, and other mycobacteria, are at the forefront of their field. Their promising new research lines offer hope against a disease that continues to kill thousands of people year after year.Bacterial metabolism may cause intrinsic drug resistance. However, it can also transform inactive parent drugs into bioactive derivatives. This is the case with several antimycobacterial prodrugs. These "prodrugs", which are biologically inactive compounds, are broken down by bacteria to make effective byproduct compounds within the bacteria cell.In the paper, scientists demonstrate that intra-bacterial metabolism (TA-C), a new Mycobacterium tuberculosis dihydrofolate reducer (DHFR) inhibitor, increases its on-target activity by up to two orders of magnitude. The TB germ metabolizes TA-C, but its function is inhibited by the byproducts.This is the first antimycobacterial 'prodrug-like-like' that has baseline activity without intracellular bioactivation. The authors describe the mechanism in their latest paper and provide the foundation for a new class of DHFR inhibitors. They also discover a new antibacterial drug discovery strategy.This new method could prove crucial in the fight against TB. It kills 1.3 millions people worldwide each year and disproportionately affects the developing world. To combat drug-resistant strains, new drugs are urgently needed.###The CDI team consisted of Dr. Wassihun Wedajo Aragaw from the Dick lab, who discovered the mechanism of action, and Drs. Veronique Dartois and Martin Gengenbacher were joined by Matthew D. Zimmerman. Brendon Lee from the Australian National University and Colin Jackson of the National University of Singapore were part of the international team that collaborated with CDI. Xuan Yang, Wai-Keung Chui and Xuan Yan also participated in the collaboration.Dick and Chui published a 2017 paper describing the TA–C compound's effectiveness against TB bacteria.
