Discovery of new metabolic pathway offers TB treatment hope

25 June 2013

Mycobacterium tuberculosis.

Image: Mycobacterium tuberculosis. Transmission electron micrograph (TEM) of Mycobacterium tuberculosis bacteria. It is a rod- shaped bacillus that causes tuberculosis (TB) in humans.©  PASIEKA/SCIENCE PHOTO LIBRARY

Researchers have discovered a new metabolic pathway in the bacterium that causes tuberculosis (TB) in humans, which might help it to obtain nutrients from its host, evade the immune system and ultimately cause this deadly disease. 

The research, by a team at the MRC's National Institute for Medical Research (NIMR; now part of the Francis Crick Institute), may open up a new avenue for TB treatment, by finding antibiotics that specifically target this pathway. 

Dr Luiz Pedro de Carvalho of NIMR explained: "Novel drugs against new targets are urgently needed to treat the increasing spread of strains of Mycobacterium tuberculosis, the bacterium that causes human TB, that are resistant to currently available drugs. 

"Validated targets for drug discovery are essential for the successful development of new drugs. Therefore, our findings and future experiments will be essential to the development of new antibiotics targeting this unexplored pathway." 

Dr de Carvalho's team at NIMR worked with colleagues from the University of Michigan in the USA to study previously unknown proteins in the genome of M. tuberculosis and to investigate what they do. They used a new screening method called 'metabolomic profiling', which allows hundreds of metabolites to be separated, identified and quantified simultaneously. The scientists then carried out follow-up genetic, biochemical and structural studies to confirm their findings. 

They found an unexpected enzyme called glycerol phosphate phosphatase (GPP), which led to the discovery of a previously completely unknown metabolic pathway in M. tuberculosis. 

Dr de Carvalho said: "We are now evaluating the importance of this GPP and its related metabolic pathway in experimental models of infection. If the enzyme and pathway turn out to be important for infection, this will open a new avenue for target-based antibiotic discovery against M. Tuberculosis." 

"Our study highlights the abundance of enzymatic reactions and biochemical pathways to be discovered, even in well characterised pathogens such as M. tuberculosis." 

The paper, Discovery of a glycerol3-phosphate phosphatase reveals glycerophospholipid polar head recycling in Mycobacterium tuberculosis, is published in the Proceedings of the National Academy of Sciences.

  • MRC scientists have identified a new enzyme and related metabolic pathway in the bacterium that causes human TB, opening up the possibility of new treatment targets for this increasingly antibiotic-resistant disease. 
  • Metabolic pathways are a series of chemical reactions that occur inside cells that allow various processes to occur. They require the activity of enzymes to occur, such as the one discovered in this study. 
  • The team used a new method called 'metabolomic profiling' to identify the protein and its function. The metabolic pathway they discovered was previously unknown despite decades of research into M. tuberculosis and its genome having been available to scientists for 10 years. 
  • According to the WHO, TB is second only to HIV/AIDS as the greatest killer worldwide due to a single infectious agent. In 2011, it killed 1.4 million people and caused illness in 8.7 million.