New toxin discovered by research team lead by Durham University to be used to make anti-TB drugs

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Durham University along with the Laboratory of Molecular Microbiology and Genetics/Centre Integrative Biology in Toulouse, France, are leading a team of international researchers to develop new anti-Tuberculosis (TB) drugs.

The team is aiming to exploit a toxin, discovered by scientists, in the germ itself, to kill the TB bacteria. This toxin can block the use of important amino acids required by the bacteria to produce essential proteins needed for survival.

The new findings of the research have been published in the journal Science Advances.

Tuberculosis is the deadliest infectious disease in the world today, killing 1.5 million people annually. It can affect any part of the human body, including the nervous system, bones and glands. However, it primarily attacks the lungs. TB is an airborne disease so it spreads in tiny droplets, released from the coughs or sneezes of an infected person. 

Tuberculosis is deadliest infectious disease in the world today, killing 1.5 million people annually.

To adapt to the stress in the environment, bacteria produce toxins. Normally counteracted by a matching antidote, when active they have the potential to decelerate growth and even lead to cell death. 

The research team discovered a new toxin produced by the TB bacterium Mycobacterium tuberculosis called MenT. 

By developing a detailed 3-D picture of MenT and combining it with genetic and biochemical data, it was discovered that the new toxin inhibits the use of amino acids needed by the bacteria to produce protein. If it is not neutralised by its MenA anti-toxin, MenT stalls the growth of Mycobacterium tuberculosis, causing the bacteria to die.

Dr Tim Blower, Associate Professor in the Department of Biosciences, and Co-Senior Author and Lister Institute Prize Fellow at Durham University, said that tuberculosis was effectively “actively poisoning itself” in the process. He said: “Through the forced activation of MenT, or by destabilising the relationship between the toxin and its anti-toxin MenA, we could kill the bacteria that cause TB.

Funded in the UK by a Springboard Award from The Academy of Medical Sciences, the research also involved The Institute of Pharmacology and Structural Biology, Toulouse, and the Institute of Physico-Chemical Biology, Paris, France; and the University of Otago, New Zealand.

“Effectively the tuberculosis is actively poisoning itself.”

Dr Tim Blower

NRS Research Director at the Laboratory of Molecular Microbiology and Genetics/Centre Integrative Biology, CNRS/Toulouse University Dr Pierre Genevaux, the Co-Senior author said that the research identified a “previously unknown mechanism” that could potentially “block protein synthesis and treat tuberculosis and other infection.” 

“This work opens up new avenues of research and discovery for the next generation of drugs.”

Image: High-resolution structures of the MenT3 (blue) and MenT4 (pink) protein toxins, overlaid to show their similarity. Credit: Ben Usher, Dr Tim Blower.

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