Blocking Nitrogen Metabolism in TB
Timothy Wencewicz, Ph.D.
Center for Metabolism and Immunity, Center for Pediatric Pulmonary Disease
Interdisciplinary Research Initiative
2/1/2018 - 1/31/2021
Christina Stallings, Jeffrey Henderson
Worldwide, mycobacteria are the most common cause of pulmonary infection in children. Mycobacterium tuberculosis (Mtb) infects >1 million children annually and accounts for >210,000 deaths annually. In addition, non-tuberculosis mycobacteria (NTM) pathogens are causing an increasing number of pulmonary infections in children with cystic fibrosis. Mycobacteria survive inside host cells, which makes them innately hard to treat. Additionally, antibiotic resistance is on the rise in Mtb and NTM infections. New therapeutic agents are desperately needed to improve treatment outcomes and overcome resistance. Glutamine synthetase (GS) is required to supply L-glutamine during infection and drive nitrogen metabolism. This project aims to develop novel GS inhibitors to deplete L-glutamine and potentiate the activity of clinical antibiotics against resistant Mtb and NTM pathogens.
Proposed specific aims
· Synthesize and optimize GS inhibitors and prodrugs as anti-mycobacterial agents with improved safety and efficacy.
· Investigate effects of GS inhibitors on nitrogen metabolism in mycobacteria.
· Determine synergism of our GS inhibitors with clinical antibiotics.
Potential impact on child health
These innovative approaches will provide GS inhibitors and prodrugs as novel second-line agents to enhance the current standard of care and improve the outcomes in children.