Serum-Stable, Cationic, α-Helical AMPs to Combat Infections of ESKAPE Pathogens and C. albicans

Expedition in the rate of development of antimicrobial resistance accompanied by the slowdown in the development of new antimicrobials has led to a dire necessity to develop an alternate class of antimicrobial agents. Antimicrobial peptides (AMPs), available in nature, are effective molecules that can combat microbial infections. However, due to several inherent shortcomings such as salt sensitivity of their potency, short systemic half-lives owing to protease and serum degradation, and cytotoxicity, their commercial success is limited. Inspired by α helical AMPs present in nature, here in this work, we have developed two short, cationic, helical AMPs RR-12 and FL-13. Both peptides exhibited high broad-spectrum antimicrobial activity, salt tolerance, prompt bactericidal activity, considerable serum stability, remaining non-cytotoxic and non-hemolytic at relevant microbicidal concentrations. The designed AMPs were membranolytic toward the microbial strains, though there were subtle differences in the mechanism owing to the variation in the composition of the cell membranes in different microbes. Rigorous experimental techniques and molecular dynamics (MD) simulations were performed to understand the structure, activity, and their mechanisms in detail. Positive charge, balanced hydrophobicity-hydrophilicity, and helical conformation were the different attributes that led to the development of the superior performance of the AMPs, making them valuable additions to the repertoire of therapeutically promising antimicrobials.