Discovery of nitrogen source for TB bacteria may lead to new drug targets

29 September 2013

Ball-and-stick representation of aspartate.

Image: Ball-and-stick representation of aspartate.

For the first time, scientists have discovered how the bacterium that causes tuberculosis (TB) takes up nitrogen, a nutrient that is crucial for it to replicate, infect people and spread. 

The research may help in the development of new drugs to fight this devastating illness. 

GĂ©rald Larrouy-Maumus and Luiz Pedro de Carvahlo of the MRC's National Institute for Medical Research (now part of the Francis Crick Institute)  worked with colleagues from the University of Toulouse, the Institute of Pharmacology and Structural Biology at the National Centre for Scientific Research and INSERM, all in France. 

Dr de Carvahlo explained: "Nitrogen is a key element for nutrition and is present in almost all biological molecules, such as amino acids, which make up proteins, nucleosides, which make up DNA and RNA and vitamins. This means that Mycobacterium tuberculosis needs to take up nitrogen from the human host, its sole natural reservoir." 

Until now, it has been unclear what this source of nitrogen is or what transport systems the bacterium uses for nitrogen uptake. An improved understanding of the metabolic requirements of M. tuberculosis during infection of a host may offer new targets for treatments against the disease in the future. 

For their study, the team combined classic genetics and bacterial physiology methods with newer imaging techniques and 'metabolomic profiling' (see box) to investigate the role of a protein called AnsP1, which they discovered was a transporter for the amino acid aspartate. The scientists found that AnsP1 plays a key role in acquisition of nitrogen by the bacteria, and is important during infection. Together, the results indicate that aspartate is a primary source of nitrogen for M. tuberculosis.

Dr de Carvahlo said: "Until this study, no one knew what nitrogen sources were being used by M. tuberculosis during infection of a human host. This study provides the first evidence for how M. tuberculosis obtains nitrogen, as aspartate, from its host.

"The validation of essential genes, such as those required during infection, is a key step towards target-based drug discovery. As we now understand the importance of aspartate and AnsP1 during infection, we can try to develop drugs that block this transporter, with the ultimate aim of treating tuberculosis."

The paper, Aspartate is required for Mycobacterium tuberculosis nitrogen assimilation and host colonization, is published in Nature Chemical Biology.

 

  • As for all organic life forms, nitrogen is a key nutrient for the bacterium that causes tuberculosis (TB), Mycobacterium tuberculosis.MRC scientists have now discovered one main source of nitrogen, in research that offers hope for new treatment targets. 
  • 'Metabolomic profiling', used in this study, is a new screening method, which allows hundreds of metabolites to be separated, identified and quantified simultaneously. Metabolites are biological molecules involved in and produced by metabolism - the chemical reactions used by cells to turn nutrients into energy and other molecules. 
  • TB is second only to HIV/AIDS as the greatest killer worldwide due to a single infectious agent. WHO statistics show that in 2011, it killed 1.4 million people and caused illness in 8.7 million.