Understanding bacterial 'suicide' mechanism to develop drugs for tuberculosis

Understanding bacterial 'suicide' mechanism to develop drugs for tuberculosis


The bacteria responsible for tuberculosis can be killed by a toxin they produce unless it is neutralized by an antidote protein. Their findings are published in Molecular Cell. The team is now seeking to appropriate this "suicide" mechanism for therapeutic purposes.

Bacteria synthesize molecules that are toxic to themselves. When exposed to a harsh environment, these toxins slow the growth of the bacterial population until more favorable conditions develop. Some toxins even kill the bacteria that produced them. The biological purpose of this "suicide" is still a subject of debate. It may function as an antiviral defense mechanism, killing infected bacteria to spare uninfected neighbors. Or, when faced with nutrient scarcity, it may serve to "sacrifice" a few for the benefit of the many. Under normal conditions, bacteria produce antidote proteins that neutralize the toxins.

The researchers have identified one such "suicide toxin," called MbcT, in the bacteria responsible for tuberculosis, Mycobacterium tuberculosis. If not thwarted by its antitoxin, MbcA, the MbcT toxin will kill M. tuberculosis by breaking down its store of NAD--a small molecule critical to sustaining life--through a newly identified reaction. MbcT catalyzes NAD+ degradation in vitro and in vivo. Unexpectedly, the reaction is stimulated by inorganic phosphate, and authors reveal that MbcT is a NAD+phosphorylase.

The team of researchers has demonstrated the therapeutic potential of this toxin. They infected human and mouse cells with a strain of M. tuberculosis lacking this toxin/antitoxin system--but in which they could artificially trigger production of the MbcT toxin. Toxin activation drastically reduced the number of bacteria infecting the cells and increased the mouse survival rate.

These findings pave the way for a novel treatment targeting tuberculosis, which remains one of the top ten causes of death worldwide. And the antibiotic resistance developed by certain strains of Mycobacterium tuberculosis only underscores the urgency.

The researchers have already determined the 3D structure of the MbcT-MbcA complex, and the different teams are now striving to identify compounds that can free the toxin from the antidote with which it is coupled. found that MbcT resembles secreted NAD+-dependent bacterial exotoxins, such as diphtheria toxin. Indeed, These molecules may also help fight other infectious diseases because analogous toxin/antitoxin systems have been detected in other pathogenic bacteria.

http://www.cnrs.fr/en/tuberculosis-commandeering-bacterial-suicide-mechanism

https://www.cell.com/molecular-cell/fulltext/S1097-2765(19)30048-6

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