This unique functionality of the TA system has been
investigated by a collaborative international team of scientists from EMBL,
Germany, IPBS/CNRS/ University of
Toulouse, France, and The Francis Crick Institute, UK. Importantly, this team
of scientists has just determined the high-resolution structure of the TA
system, which has been published in
, a Cell Press publication.
The study was led by Dr. Matthias Wilmanns, Ph.D, and Dr. Annabel Parret,
Ph.D. Dr. Wilmanns is a Senior Scientist and Group Leader, while Dr. Parret is
a Staff Scientist in his Group at the European Molecular Biology Laboratory
(EMBL), Hamburg, Germany.
Their collaborators included scientists from Dr. Olivier Neyrolles' Group at the Institute of Pharmacology and
Structural Biology (IPBS), National Center for Scientific Research
(CNRS)/University of Toulouse, France, as well as scientists from Dr. Luiz
Pedro Carvalho's Group at The Francis Crick Institute, London, UK.
What is the Tuberculosis Bacteria's Toxin-Antitoxin (TA)
genome has 80 TA systems, consisting of closely interlinked genes that encode a
toxin (toxic protein) and an antitoxin, which is capable of neutralizing the
toxin. Under normal conditions, the activity of the toxin is kept in check by
the bound antitoxin in the TA complex.
However, when the bacteria are under
stress such as when nutrients become limited, specific enzymes present in the
bacterial cells degrade the antitoxin, thereby removing its inhibitory effect
on the toxin. As a result, the activated toxin molecules slow down the
growth of the bacteria,
so that they can survive in the harsh and stressful
A specific type of TA system exhibits a
more extreme effect when the antitoxin molecules are degraded. In this case,
the toxin molecules actually kill the bacterial cells, thereby essentially
making the cells commit suicide. Thus, this particular TA system could be a
potential drug target for therapeutic purposes.
That is why the research
team was interested in taking a closer look at the structure of this TA system.
Determination of the Structure of the TA System
The high-resolution structure of the TA
system was determined by the lead author, Dr. Diana Mendes Freire, PhD, who was
previously at EMBL, but is currently a Project Officer at Ciência
Viva in Lisbon, Portugal.
Freire solved the structure of the TA system within a
matter of just eight months. In this regard, Parret says "Our goal was to see the TA
system's structure, so we could try to understand and even manipulate it. It
was as if we were working blindly before."
The TA system has a large compact structure that is
shaped like a double-doughnut. Wilmanns likens it to a diamond. "It looks like a diamond, and it is very
he says. Interestingly, the
molecular structure of the toxin resembles the toxins of cholera and
diphtheria, which have been responsible for hundreds of thousands of deaths
over the past century.
Importance of the Structure of
the TA System
Armed with the knowledge of the structure
of the TA system, this interdisciplinary group of scientists was able to
determine its mode of action. They found that after dissociation from the
antitoxin, the toxin becomes activated and starts to degrade crucial cellular
metabolite molecules called nicotinamide-adenine dinucleotide (NAD+
This suicidal activity eventually results in the death of the Mtb
cells. Why these bacterial cells
exhibit such a suicidal behavior has still not been worked out. However, based
on current knowledge, the TA system could be exploited as a potential drug
target for developing new treatments for TB
The results have been extremely
encouraging. "Our collaborators in
Toulouse were already able to extend the lifetime of mice infected with TB by
activating the toxin in a controlled way,"
says Parret. "If we find molecules that can disrupt the
TA system - and thus trigger cell death - in TB patients, that would be the
In order to find this "perfect drug" that
can bind to and break-up the TA complex, possibly thousands of small molecules
will need to be screened. However, it should be noted that it will be extremely
difficult to find the ideal molecule as the structure of the TA system is so
highly stable that it will be an enormous challenge to find an entry point to
break-up the complex. In spite of this, Wilmanns is still very optimistic and
says "But if we succeed, this could be a
new approach for treating TB and other infectious diseases."
- An NAD+ Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death - (https://doi.org/10.1016/j.molcel.2019.01.028)