New strategy in the fight against TB?

October 2, 2013

A new approach to combating the tubercle bacillus, the microorganism that kills some 1.5 million people in the world each year, has been developed by a French-British team including scientists from CNRS, Inserm, the Institut Curie and Université Toulouse III - Paul Sabatier. The researchers have discovered that an amino acid, aspartate, is essential for the development of the bacillus because it acts as its main source of nitrogen. They have also succeeded in establishing the mechanism by which the bacterium extracts aspartate from its host. These results, published online on 29 September 2013 in the journal Nature Chemical Biology, could make it possible to develop new antibiotics and new vaccines derived from attenuated strains of the bacillus, incapable of supplying themselves with aspartate.

Tuberculosis, an infectious disease that generally affects the lungs and kills more than 1.5 million people each year throughout the world, is caused by a bacterium known as Mycobacterium tuberculosis. A vaccine, BCG, is available against the bacillus but its efficacy is variable. Antibiotic treatments also exist, but doctors are increasingly confronted with strains that are resistant to several antibiotics, hence the need to develop new therapeutic and preventive strategies.

The researchers from the Institut de Pharmacologie et de Biologie Structurale (CNRS/Université Toulouse III - Paul Sabatier) who coordinated this work focused on the mechanisms whereby M. tuberculosis supplies itself with nitrogen, an essential element in the synthesis of a large number of biomolecules, proteins, nucleic acids and vitamins for example. They studied an amino acid transporter known as AnsP1 and showed that this transmembrane protein is responsible for capturing aspartate, an amino acid, and then introducing it into the bacterium. In fact, a mutant of the genetically inactivated bacillus in this transporter proved incapable of growing in a medium containing aspartate as unique nitrogen source. The researchers then tried to determine whether aspartate really is an important source of nitrogen for the bacillus. To do so, they used a technique that makes it possible to map all the metabolites present in a cell. The team fed the bacilli with aspartate containing a heavy isotope of nitrogen and showed that M. tuberculosis in fact assimilates nitrogen from aspartate, which is then found in numerous molecules synthesized by the microorganism.

Using a small-molecule imaging technique, the researchers showed that when macrophages (cells of the immune system present in large quantities in the pulmonary tract) infected by the bacillus were placed in contact with aspartate containing heavy nitrogen, the heavy isotope ended up in the pathogen. In other words, AnsP1 allows the bacillus to capture from its host cell. In in vivo experiments, the researchers infected mice with a bacillus in which AnsP1 was inactivated. Surprisingly, this bacillus strain proved to be highly attenuated: it multiplied more slowly and caused much less damage than normal strains to the lungs of the mice models. This highlights the unsuspected role of this aspartate transporter in the virulence of the mycobacterium.

AnsP1 and the other molecules involved in the metabolism of aspartate could therefore be potential targets for . Furthermore, this mutant strain in which AnsP1 has been inactivated could turn out to be a good candidate for the development of novel vaccines capable of providing better and longer protection than BCG.

Explore further: Discovery of new genes involved in the parasitism of cells by the tubercle bacillus

More information: Mycobacterium tuberculosis nitrogen assimilation and host colonization require aspartate, Alexandre Gouzy, Gérald Larrouy-Maumus, Ting-Di Wu, Antonio Peixoto, Florence Levillain, Geanncarlo Lugo-Villarino, Jean-Luc Gerquin-Kern, Luiz Pedro Sório de Carvalho, Yannick Poquet & Olivier Neyrolles. Nature Chemical Biology.

Related Stories

Heavy metals boost immunity

September 21, 2011

A new natural defense mechanism against infections has been evidenced by an international team led by researchers from CNRS, Inserm, the Institut Pasteur and the Universite Paul Sabatier – Toulouse III. Zinc, a heavy ...

Better vaccines for tuberculosis could save millions of lives

August 28, 2012

Cases of one of the world's deadliest diseases—tuberculosis—are rising at an alarming rate, despite widespread vaccination. Reasons for the ineffectiveness of the vaccine, especially in regions where this infectious disease ...

Researchers identify a new mechanism of TB drug resistance

June 12, 2013

Pyrazinamide (PZA)—a frontline tuberculosis (TB) drug—kills dormant persister bacteria and plays a critical role in shortening TB therapy. PZA is used for treating both drug susceptible and multi-drug resistant TB (MDR-TB) ...

Key to tuberculosis cure lies in the starving of the enemy

August 12, 2013

Scientists at the University of Surrey have undertaken research into tuberculosis which could result in quicker treatment for sufferers and potentially reduce the problem of drug-resistance. The study was recently published ...

Recommended for you

Immune breakthrough: Unscratching poison ivy's rash

August 23, 2016

We all know that a brush with poison ivy leaves us with an itchy painful rash. Now, Monash University and Harvard researchers have discovered the molecular cause of this irritation. The finding brings us a step closer to ...

Zika infection may affect adult brain cells

August 18, 2016

Concerns over the Zika virus have focused on pregnant women due to mounting evidence that it causes brain abnormalities in developing fetuses. However, new research in mice from scientists at The Rockefeller University and ...

Monkeys with Sudan ebolavirus treated successfully

August 22, 2016

Scientists funded by the National Institutes of Health (NIH) have successfully treated monkeys several days after the animals were infected with Sudan ebolavirus (SUDV). The study is important, according to the researchers, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.