Characterization of the protein-protein interactions of the type-II toxin-antitoxin system ParDE1 from Pseudomonas aeruginosa

Abstract

The emergence of multidrug-resistant bacteria has led to an ever-growing antibiotic resistance crisis. To combat this growing crisis, new strategies for controlling bacterial cell growth must be developed. An underdeveloped target for new antimicrobial therapeutics are toxin-antitoxin (TA) systems. TA systems are widely dispersed genetic operons in prokaryotes which consist of a non-secreted protein (toxin) which targets essential metabolic enzymes causing cell death. The toxin’s cellular toxicity is neutralized by its cognate antitoxin (RNA or protein). In the case of type-II TA systems, the toxin protein is neutralized by directly binding to a protein antitoxin forming a toxin-antitoxin complex. The work presented within this dissertation aims to address several gaps in understanding how the protein-protein interactions of type-II TA systems are formed and maintained, with long term goals of targeting these protein-protein interactions to develop new means to control bacterial cell growth. This work focuses on the ParDE1 TA system from Pseudomonas aeruginosa, composed of the ParE toxin protein which targets DNA Gyrase.