According to the annual report of the World Health Organization (WHO), around 10 million people worldwide fell ill with tuberculosis (TB) in 2017; TB deaths are estimated at 1.3 million among HIV-negative people; and 300,000 TB deaths among HIV-positive people. Men (5.8 million) were afflicted more often than women (3.2 million) and children (1 million).
Less widespread in the West
Overall, tuberculosis is still one of the top 10 leading causes of death worldwide. Yet, an international research team led by the Wilmanns Group, part of the European Molecular Biology Laboratory (EMBL) in Hamburg may now have found a way to successfully treat and to at least interrupt the disease.
Mycobacterium tuberculosis, the TB pathogen in humans, contains 80 so-called toxin-antitoxin systems (TA systems), e.g. gene pairs that are closely linked to each other and conceal a toxic protein and an antitoxin which is a protein that blocks the toxin. Normally, the presence of the antitoxin prevents the growth of the toxin, however, under stressful conditions special enzymes can rapidly deteriorate the antitoxin molecules and thus activate the respective toxin proteins in the cell. However, generally speaking, the bacteria remain to survive due to a decrease in growth of most TA pairs and it’s not stopped completely.
Nevertheless, the effects of toxin activation could be more severe in a specific TA pair as it could kill tuberculosis cells without the antitoxin. As this reaction opens up possibilities for new curative approaches, researchers from EMBL Hamburg, IPBS from the CNRS/Université de Toulouse and the Crick Institute in London joined forces to investigate this TA system more closely.
“Our goal was to analyse the structure of the TA system in order to understand and perhaps even manipulate it. It felt as though we were blinded before,” says Annabel Parret, EMBL scientist from the Wilmanns group. The first author of the study, Diana Freire, was able to elucidate this high-resolution structure within only eight months and published this in the Molecular Cell journal.
“This structure appears to be very stable and won’t be easy to crack,” explains EMBL group leader Matthias Wilmanns. The complex has a similar structure to the toxins of cholera and diphtheria, diseases that caused epidemics with hundreds of thousands of deaths not so long ago.
These similarities have given the team the advantage to uncover the mechanism and action details of the TA structure. “The toxin degrades an important cellular metabolic product called NAD+ and therefore removes it from metabolism,” states the study. However, the question as to why bacteria have a significant “suicidal structure” is still a mystery to the scientists.
Success with mice
“Our cooperation partners in Toulouse have already been able to extend the lifespan of TB-infected mice by activating the toxin in a controlled manner,” says Parret. “If we succeed in finding molecules in tuberculosis patients that are capable of disrupting the TA system – and thus triggering the death of this cell – this could possibly lead to the development of a promising drug.
However, more research is needed before this method could be applied to other diseases. In cooperation with the drug discovery alliance and a leading biotech company, the team is, therefore, planning to examine this capability in thousands of small molecules. Still, the TA system’s structure is very stable and it will be challenging to find an entry point through which it could be opened.
“Together with our research partners, we are trying to understand the natural mechanism that leads to the release of the tuberculosis bacterium’s deadly toxin from its antidote and thus activates it. If we succeed,” says Wilmanns, “this could be a new and very promising approach to the treatment of TB and other infectious diseases.”
The project was a cooperation between researchers from the Wilmanns Group at EMBL Hamburg and the Neyrolles Group at IPBS, CNRS/Université de Toulouse, in which the Carvalho Group from the Francis Crick Institute in London also participated. The research team has established a partnership through EMBLEM’s technology transfer unit to work on the development of a potential TB drug.