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: Key to tuberculosis cure lies in the starving of the enemy

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

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 ...

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) ...

Resistance to visceral leishmaniasis: New mechanisms involved

May 16, 2013
Researchers from CNRS, Université Toulouse III - Paul Sabatier and IRD have elucidated new molecular mechanisms involved in resistance to visceral leishmaniasis, a serious parasitic infection. They have shown that dectin-1 ...

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 ...

Recommended for you

Google searches can be used to track dengue in underdeveloped countries

July 20, 2017
An analytical tool that combines Google search data with government-provided clinical data can quickly and accurately track dengue fever in less-developed countries, according to new research published in PLOS Computational ...

MRSA emerged years before methicillin was even discovered

July 19, 2017
Methicillin resistant Staphylococcus aureus (MRSA) emerged long before the introduction of the antibiotic methicillin into clinical practice, according to a study published in the open access journal Genome Biology. It was ...

New test distinguishes Zika from similar viral infections

July 18, 2017
A new test is the best-to-date in differentiating Zika virus infections from infections caused by similar viruses. The antibody-based assay, developed by researchers at UC Berkeley and Humabs BioMed, a private biotechnology ...

'Superbugs' study reveals complex picture of E. coli bloodstream infections

July 18, 2017
The first large-scale genetic study of Escherichia coli (E. coli) cultured from patients with bloodstream infections in England showed that drug resistant 'superbugs' are not always out-competing other strains. Research by ...

Ebola virus can persist in monkeys that survived disease, even after symptoms disappear

July 17, 2017
Ebola virus infection can be detected in rhesus monkeys that survive the disease and no longer show symptoms, according to research published by Army scientists in today's online edition of the journal Nature Microbiology. ...

Mountain gorillas have herpes virus similar to that found in humans

July 13, 2017
Scientists from the University of California, Davis, have detected a herpes virus in wild mountain gorillas that is very similar to the Epstein-Barr virus in humans, according to a study published today in the journal Scientific ...

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.