Site-Specific Isopeptide Bond Formation: A Powerful Tool for the Generation of Potent and Nontoxic Antimicrobial Peptides

Antimicrobial peptides (AMPs) have the potential to treat multidrug-resistant bacterial infections. However, the clinical application ofAMPs is prevented by their toxicity and poor proteolytic stability. Here, a site-specific approach is used to generate new AMPs to improve their efficacy againstbacterial pathogens while reducing their toxicity. We modified and generated a newseries of antimicrobial peptides from the leucine- and lysine-rich antimicrobialpeptide Amp1L (LKLLKKLLKKLLKLL) by the site-specific incorporation of anisopeptide bond while retaining the peptide's size, sequence, charge, and molecularweight. This single bond switch provides the peptides with a weak helicalconformation, strong antimicrobial activity, resistance to proteolytic degradation,low toxicity, and lower hemolytic activity. This new site-specific approach offers a powerful tool for developing potent and nontoxic antimicrobial drugs