Probing the specificity of toxins from type II toxin- antitoxin systems

PI: Michael Laub, Howard Hughes Medical Institute, MIT

Many bacterial pathogens can survive antibiotic treatment by entering a dormant, non-proliferative state as most antibiotics only kill actively growing cells. These so-called persister cells are not heritably resistant, but can nevertheless survive transient antibiotic treatments to re-establish infections. How cells enter into and maintain this dormant state remains poorly understood, but frequently involves toxin-antitoxin systems. When liberated from their cognate antitoxins, these toxins can suppress cell growth in a variety of ways. Bacterial genomes typically encode many toxins that are closely related to each other. Why an organism encodes multiple, related toxins and how these toxins are coordinated is unknown. We will use a combination of methods, including new RNA-seq-based methods, to systematically map the target specificities of two classes of toxins, endoribonucleases and acetyltransferases. Additionally, using structure-and sequence-based analyses, we will determine the residues within each family of toxin responsible for their specificity. This work will provide important new insights into toxin-antitoxin systems and lay the foundation for future work examining their coordinated activities during bacterial persistence.

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