Insights into the Mechanism of Antimicrobial Activity of Seven-Residue Peptides

Antimicrobial peptides have gained widespread attention as an alternative to the conventional antibiotics for combating microbial infections. Here, we report a detailed structure–function correlation of two nontoxic, nonhemolytic, and salt-tolerant de novo designed seven-residue leucine–lysine-based peptides, NH2LKWLKKLCONH2 (P4) and NH2LRWLRRLCONH2 (P5), with strong antimicrobial and antifungal activity. Biological experiments, low- and high-resolution spectroscopic techniques in conjunction with molecular dynamics simulation studies, could establish the structure–function correlation. The peptides are unstructured both in water and in bacterial membrane mimicking environment, suggesting that the secondary structure does not play a major role in their activity. Our studies could justify the probable membranolytic mode of action for killing the pathogens. Attempts to understand the mode of action of these small AMPs is fundamental in the rational design of more potential therapeutic molecules beyond serendipity in the future.