Understanding Nitrogen Metabolism to Revolutionize Tuberculosis Treatment

Metabolic network showing carbon and nitrogen metabolism. Pathways of carbon and nitrogen metabolism include glycolysis (EMP), pentose phosphate pathway (PPP), tricarboxylic acid (TCA) cycle, and anaplerotic reactions (ANA). Nitrogen source ammonium; carbon source glycerol. Reactions and metabolites involving nitrogen are shown in red. The inset (Appendix Fig S1 enlarged version) shows the last bifurcated step of the arginine biosynthesis, according to the genome-scale metabolic model sMTB2.0 (López-Agudelo et al, 2020). Citrulline is aminated either by free nitrogen to form arginine (arginine deiminase, ARCA), or aspartate is acting as nitrogen donor and arginine is formed via a two-step reaction with the intermediate argininosuccinate (argininosuccinate synthase (ARGG) and argininosuccinate lyase (ARGH)). Because the carbon backbone is the same for both branches, 13C labeling alone is not able to resolve the fluxes of either of these pathways. Credit: Molecular Systems Biology (2023). DOI: 10.15252/msb.202211099

Tuberculosis (TB) is a serious infectious disease that affects millions of people worldwide. In recent years, drug resistance has become a significant challenge in the treatment of TB, and there is an urgent need to develop new drugs to target the bacterium that causes the disease. Now, researchers from the University of Surrey have made an important discovery that could help us better understand how the bacterium survives and causes disease.

The Study

The Surrey study used a technology called fluxomics to investigate how cells process nitrogen, which is essential for the survival of the bacterium that causes TB, Mycobacterium tuberculosis (Mtb). In the most comprehensive study of its kind, the researchers tracked both carbon and nitrogen atoms within Mtb cells for the first time, using a new fluxomic tool called Bayesian 13C15N-metabolic flux analysis. They then identified the crucial role that the amino acid glutamate plays within the nitrogen metabolism in Mtb, providing an important target for new drug development.

Implications for TB Treatment

The discovery of the important role of nitrogen metabolism in Mtb survival could pave the way for new drug treatments for TB. In particular, targeting the amino acid glutamate could disrupt the nitrogen metabolism and curb the spread of the disease. The research team hopes that this new understanding of nitrogen metabolism will lead to the development of more effective drugs to tackle TB.

Commentary from the Research Team

Dr. Khushboo Borah Slater, co-author of the study and research fellow from the University of Surrey, emphasized the urgent need for new drugs to treat TB, given the growing threat of drug resistance. She stated that "using drugs to target the nitrogen metabolism could be a novel way to disrupt how the bacterium survives, multiplies and spreads inside the human host cell."

Professor Johnjoe McFadden, co-author of the study from the University of Surrey, explained that the technology they developed will play a crucial role in learning more about the carbon and nitrogen metabolisms in any living organisms, and could pave the way for more effective drug treatments being created for other human diseases.

Journal Information: Khushboo Borah Slater et al, One‐shot 13 C 15 N ‐metabolic flux analysis for simultaneous quantification of carbon and nitrogen flux, Molecular Systems Biology (2023). DOI: 10.15252/msb.202211099