Investigation of the YefM-YoeBSa toxin-antitoxin systems as novel antibacterial targets

toxin-antitoxin system;antibacterial

Larson, Amy ; Hergenrother ; Paul J.

关键词: toxin-antitoxin system;    antibacterial;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/44445/Amy_Larson.pdf?sequence=1&isAllowed=y

美国|英语

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

【 摘 要 】

The rise and spread of drug-resistant pathogens has created a critical need for the continued discovery and development of new antibacterial compounds. Bacterial toxin-antitoxin (TA) systems consist of a toxin capable of arresting cell growth and an antitoxin that binds to and inhibits the toxin under normal circumstances. Cellular stress causes a shift in the toxin/antitoxin ratio to favor the free toxin, which is released to act on its cellular target and arrest growth. TA systems therefore present potential targets for novel antibiotics, as a molecule with the capacity to artificially induce toxin activation could have an antibacterial effect. Described herein is the investigation of the Staphylococcus aureus YefM-YoeBSa1 and YefM-YoeBSa2 TA systems as targets for this artificial activation strategy. Following establishment of the prevalence, conservation, and transcription of the yefM-yoeBSa1 and yefM-yoeBSa2 genes in clinical isolates of methicillin-resistant S. aureus, a peptide activator of the YefM-YoeBSa1 TA system was sought by screening phage-displayed peptide libraries against the YefMSa1 antitoxin. Additionally, a novel strategy was devised to express the YoeBSa1 toxin in an inactive, non-toxic form. Characterization of the activity of YoeBSa1 led to the design of a fluorogenic substrate that can be used to screen for activators of this toxin in a high-throughput manner.