Abstract
Antibiotic resistance is an escalating global concern, necessitating the development of novel antibiotics with unique mechanisms of action, and preferably also with a lowered propensity for resistance development. Type-I Toxin-Antitoxin (TA) systems that are ubiquitous in bacterial genomes consist of a genetic toxin element encoding a hydrophobic peptide and an antitoxin element producing an sRNA that inhibits the toxin translation. Although the biological roles of these membrane-associated toxins remain incompletely understood, their inherent lethality upon overexpression suggests a potential as antimicrobial agents. In this study, we explore the ShoB toxin from the shoB-ohsC TA system in Escherichia coli (E. coli) as a basis for designing synthetic antimicrobial peptides for exogenous delivery. We demonstrate that ShoB-derived peptides can retain antimicrobial efficacy when modified into shorter, cationic analogs with enhanced solubility. Our most promising hits exhibit rapid bactericidal action and frequency of resistance within E. coli cultures indicate a limited tendency for resistance development. These findings highlight that type-I TA systems constitute a novel source of potential peptide-based antibiotics, thereby offering an alternative largely unexplored strategy to combat antibiotic-resistant bacterial infections.