**Suicide system in tuberculosis bacteria might hold key to treatment

February 18, 2019, European Molecular Biology Laboratory
The high-resolution structure of the toxin-antitoxin system. Credit: EMBL Hamburg

Tuberculosis (TB) is one of the top 10 causes of death worldwide. In 2017, 10 million people around the world fell ill with TB and 1.3 million died. The genome of the bacterium that causes TB holds a special toxin-antitoxin system with a surprising function: Once the toxin is activated, all bacterial cells die, stopping the disease. An international research team co-led by the Wilmanns group at EMBL in Hamburg investigated this promising feature for therapeutic targets. They now share the first high-resolution details of the system in Molecular Cell.

Mycobacterium tuberculosis is the bacterium that causes TB in humans. Its genome holds 80 so-called toxin-antitoxin (TA) systems, sets of closely linked genes that encode both a toxic protein and an antitoxin—a toxin-neutralising antidote.

When the bacteria are growing normally, toxin activity is blocked by the antitoxin's presence. But under stress conditions such as lack of nutrients, dedicated enzymes rapidly degrade the antitoxin molecules. This activates the toxin proteins in the cell and slows down the growth of the bacteria, allowing them to survive the stressful environment.

One particular TA system has a more drastic effect: in the absence of the antitoxin, the toxin kills the bacteria. As this system holds potential for therapeutic targets, researchers from EMBL Hamburg, the IPBS at the CNRS/Université de Toulouse, and the Crick Institute in London joined forces to study this TA system in more detail. "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," says Annabel Parret, EMBL staff scientist in the Wilmanns group, who led the project.

Illustration shows sections of Mycobacterium tuberculosis bacteria. The Pac-Man symbolizes the toxin, which in the absence of its antitoxin counterpart, 'eats up' the NAD+, causing the cell to die. In the bacterium in the back, the Pac-Man's mouth is blocked by the antitoxin, preventing the degradation of NAD+ and allowing the cell to grow normally. Credit: Beata Edyta Mierzwa

The high-resolution structure—solved within eight months by first author Diana Freire—revealed a large and compact system with a double-doughnut shape. "It looks like a diamond, and it is very stable," says EMBL group leader Matthias Wilmanns. The structure resembles the toxins of cholera and diphtheria, diseases that caused epidemics with hundreds of thousands of people dying even within the past 100 years.

Knowledge of the structure gave important guidance for further studying the system's biochemistry—a challenging part of the project. By using an interdisciplinary approach, the team was able to discover the details of the TA system's mode of action. When the toxin dissociates from its antidote, it becomes activated and starts to degrade essential cellular metabolites called NAD+ molecules. This "suicide" activity ultimately leads to the death of all bacterial cells. Why the bacteria have such a suicide system is puzzling, but there is no doubt it has the potential to be exploited as a drug target.

"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 perfect drug."

The team will now screen thousands of small molecules to see if they have this capability. However, the structure of the TA system is so stable that it will be a big challenge to find an entry point where they can go in to break it. Wilmanns says, "But if we succeed, this could be a new approach for treating TB and other infectious diseases."

Explore further: A new way of fighting bacteria?

More information: Diana Mendes Freire et al. An NAD+ Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death, Molecular Cell (2019). DOI: 10.1016/j.molcel.2019.01.028

Related Stories

A new way of fighting bacteria?

February 22, 2016

In bacteria, toxin-antitoxin systems consist of a set of two closely linked genes. Situated on the same chromosome, they encode both a protein 'poison' and a counteracting 'antidote'. Under normal conditions, the antitoxin ...

Oxygen can wake up dormant bacteria for antibiotic attacks

December 8, 2016

Bacterial resistance does not come just through adaptation to antibiotics, sometimes the bacteria simply go to sleep. An international team of researchers is looking at compounds that attack bacteria's ability to go dormant ...

FIC proteins send bacteria into hibernation

August 20, 2015

Bacteria do not cease to amaze us with their survival strategies. A research team from the University of Basel's Biozentrum has now discovered how bacteria enter a sleep mode using a so-called FIC toxin. In the current issue ...

Turning bacteria against themselves

February 8, 2011

Bacteria often attack with toxins designed to hijack or even kill host cells. To avoid self-destruction, bacteria have ways of protecting themselves from their own toxins.

Recommended for you

Coffee-based colloids for direct solar absorption

March 22, 2019

Solar energy is one of the most promising resources to help reduce fossil fuel consumption and mitigate greenhouse gas emissions to power a sustainable future. Devices presently in use to convert solar energy into thermal ...

Paleontologists report world's biggest Tyrannosaurus rex

March 22, 2019

University of Alberta paleontologists have just reported the world's biggest Tyrannosaurus rex and the largest dinosaur skeleton ever found in Canada. The 13-metre-long T. rex, nicknamed "Scotty," lived in prehistoric Saskatchewan ...

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.