M. tuberculosis is the bacterial strain responsible for tuberculosis, an infectious disease that cases more than 1 million deaths worldwide every year. The development of new pharmaceuticals to treat tuberculosis, especially pharmaceuticals with new mechanisms of action, is of increasing concern as new drug-resistant strains of tuberculosis emerge.
Fumarate hydratase is a key metabolic enzyme in both bacteria and humans, as an essential part of the citric acid cycle. Researchers at NCATS used a high-throughput chemical screen of more than 400,000 small molecules to discover a unique molecule, compound 7, which effectively inhibited fumarate hydratase. While the fumarate hydratase is a common enzyme in both humans and M. tuberculosis, with a very similar structure, compound 7 inhibits only the bacterial version of fumarate hydratase.
Follow-up experiments revealed that compound 7 was acting as a dimeric inhibitor in an allosteric pocket of fumarate hydratase. To act as an effective catalyst, the C subunit of fumarate hydratase needs to close and bind to the L-malate substrate. Compound 7 effectively keeps the enzyme in the open conformation by binding between the A and C subunits. Compound 7 was then found to inhibit the growth of M. tuberculosis, but relatively high concentrations were necessary. This remains a promising lead for the development of therapeutics to treat tuberculosis.
- Clifton Barry III, Ph.D., National Institute of Allergy and Infectious Diseases, NIH
- Chris Abell, Ph.D., University of Cambridge
- Kasbekar M, Fischer G, Mott BT. Selective small molecule inhibitor of the Mycobacterium tuberculosis fumarate hydratase reveals an allosteric regulatory site. Proc Natl Acad Sci USA. 2016;113(27):7503–8.
A novel small molecule inhibitor of fumarate hydrolase with specificity for M. tuberculosis has been discovered. Future work may lead to novel treatments of tuberculosis.
Public Health Impact
Tuberculosis is a disease of serious concern, responsible for more than a million deaths worldwide every year, with antibiotic-resistant strains of tuberculosis becoming increasingly problematic. The discovery of new potential inhibitors specific to M. tuberculosis may allow for the discovery of new treatments for tuberculosis, ultimately saving thousands of lives.