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A new antitoxin mechanism could neutralize different toxins and protect bacteria from bacteriophages

A new antitoxin mechanism could neutralize different toxins and protect bacteria from bacteriophages

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The toxin-antitoxin systems are a set of two closely linked genes. One encodes the “toxin”, while the other its corresponding “antitoxin” that counteracts the toxic effect that compromises different cellular processes. They are widespread in plasmids and chromosomes of bacteria and archaea, as well as in genomes of temperate bacteriophages, viruses that prey on these microbes.

As bacteria are becoming more resistant to antibiotics, phage therapy is emerging as an alternative therapeutic strategy to fight bacterial infections. However, bacteria carry some defense mechanisms against bacteriophages, and the toxin-antitoxin system is one of them. The activation of toxins limits the growth of bacterial populations infected by bacteriophages, thus inhibiting the spread of the virus. Therefore, understanding the toxin-antitoxin systems’ mechanism and evolution is key to ensuring the success of phage therapy.

Now, researchers from the University of Lund, led by Gemma C. Atkinson, in collaboration with scientists from other Swedish universities, the United Kingdom, Estonia, Denmark, Germany, and France have found an antitoxin protein domain that has evolved to neutralize dozens of different toxins.

Their computational analysis, published by the Journal Proceedings of the National Academy of Sciences, shows that the new domain, called Panacea after the Greek goddess of universal remedy, can neutralize not only cognate toxins through direct interactions, but also the noncognate ones, indirectly. That is, Panacea is so versatile that it is able to counteract its neighboring toxins and even others outside its toxin-antitoxin pair. These in silico results were experimentally validated in Escherichia Coli cultures.

Altogether, the findings suggest that the Panacea domain could be an adaptable universal or semi-universal neutralizer with potential applications in the biotechnological industry.

«Bacteriophages are at the center of the research we carry out at Telum Therapeutics. We seek for new lytic phages enzymes able to control pathogenic antibiotic-resistant bacteria», declares Roberto Díez, CEO of Telum Therapeutics. «This work is a step forward to stopping the spread of these microbes. However, we have to think of a way to attack the bacterium that damages its vital pillars. If we make a simile with a building, in which we only break the pillars that are not master pillars, as this toxin-antitoxin system could be, the bacterium can recover (i.e., resist). The building does not fall, because workers have time to rebuild that pillar, but if we hit its master pillar, the bacterium will not be able to recover and will die quickly. This is what endolysins allow us to do, to attack the master pillar of the bacterium.»

Article reference

Tatsuaki Kurata, Chayan Kumar Saha, Jessica A. Buttress, Toomas Mets, Tetiana Brodiazhenko, Kathryn J. Turnbull, Ololade F. Awoyomi, Sofia Raquel Alves Oliveira, Steffi Jimmy, Karin Ernits, Maxence Delannoy, Karina Persson, Tanel Tenson, Henrik Strahl, Vasili Hauryliuk, Gemma C. Atkinson. «A hyperpromiscuous antitoxin protein domain for the neutralization of diverse toxin domains». Proceedings of the National Academy of Sciences, 2022; 119 (6): e2102212119 DOI: 10.1073/pnas.2102212119

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