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.