The prevalence of toxin-antitoxin systems and their tractability as novel antimicrobial targets

toxin-antitoxin;Axe-Txe;Vancomycin-resistant enterococci (VRE);Methicillin-resistant\rStaphylococcus aureus (MRSA);relBE

Moritz, Elizabeth M.

关键词: toxin-antitoxin;    Axe-Txe;    Vancomycin-resistant enterococci (VRE);    Methicillin-resistant\rStaphylococcus aureus (MRSA);    relBE;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/17030/Moritz_Elizabeth.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Large, low copy number plasmids, such as those harboring antibiotic resistancegenes, often possess plasmid maintenance systems to ensure their persistence andinheritance in a bacterial population. One example is the proteic toxin-antitoxin (TA)system, consisting of a toxin and an antitoxin encoded in a single operon. Whenexpressed, the antitoxin binds to and neutralizes the toxin. However, if during celldivision a plasmid-free daughter cell arises, the labile antitoxin is rapidly degraded,freeing the toxin to kill the cell. If TA systems are prevalent and functional in clinicallyrelevant bacteria, they could be exploited as a novel antimicrobial strategy: a smallmolecule capable of relieving the neutralizing effect of the antitoxin would free the toxinto kill the cell. This thesis research has, in part, focused on defining the prevalence of TAsystems in clinical isolates of vancomycin-resistant enterococci and methicillin-resistantS. aureus to validate TA systems as an antibacterial target. Two TA systems, Axe-Txeand RelBE, were found to be common among the pathogenic bacteria surveyed and weretherefore further investigated. A cell-based high-throughput assay was developed toscreen for small molecules that induce toxin-dependent cell death in E. coli expressingRelBE. Additionally, mechanistic studies were performed to determine the mode ofaction by which the Txe toxin causes cell death.