Addition and omission analogs of the 13-residue antibacterial and hemolytic peptide PKLLKTFLSKWIG: structural preferences, model membrane binding andbiological activities

The consequences of selective addition or deletion of polar amino acids in a 13-residue antibacterial peptide PKLLKTFLSKWIG on structure, membrane bin ding and biological activities have been investigated. The variants generat ed are (a) S and T residues replaced by K, (b) S and T residues deleted ind ividually and together, (c) introduction of two additional K and (d) deleti on of L and L with T. In the aqueous environment all the peptides were unor dered. In trifluoroethanol, the spectra of peptides belonging to groups (a- c) suggest distorted helical conformation. Peptides in group (d) appear to adopt P-sheet conformation. The peptides bind to zwitterionic and negativel y charged lipid vesicles, although to different extents. With the exception of peptides in group (d), all the other peptides exhibited comparable anti bacterial activity against Escherichia coli and Staphylococcus aureus. Howe ver, the changes made in the peptides in groups (a-c) resulted in reduction of hemolytic activity compared to the parent peptide. Extent of binding to lipid vesicles composed of phosphatidylcholine and cholesterol appears to correlate with hemolytic activity. It appears that polar and charged residu es play a major role in modulating the biological activities of the 13-resi due peptide PKLLKTFLSKWIG. The Ii-residue peptide-like PKLLKFLKWIG has sele ctive antibacterial activity. Thus, by judicious engineering it should be p ossible to generate short peptides with selective antibacterial activity.