A novel linear amphipathic beta-sheet cationic antimicrobial peptide with enhanced selectivity for bacterial lipids

All known naturally occurring linear cationic peptides adopt an amphipathic alpha -helical conformation upon binding to lipids as an initial step in t he induction of cell leakage. We designed an 18-residue peptide, (KIGAKI)(3 )-NH2, that has no amphipathic character as an alpha -helix but can form a highly amphipathic beta -sheet. When bound to lipids, (KIGAKI)(3)-NH2 did i ndeed form a beta -sheet structure as evidenced by Fourier transform infrar ed and circular dichroism spectroscopy. The antimicrobial activity of this peptide was compared with that of (KIAGKIA)(3)-NH2, and it was better than that of GMASKA-GAIAGKIAKVALKAL-NH2 (PGLa) and (KLAGLAK)(3)NH2, all of which form amphipathic alpha -helices when bound to membranes. (KIGAKI)(3)-NH2 w as much less effective at inducing leakage in lipid vesicles composed of mi xtures of the acidic lipid, phosphatidylglycerol, and the neutral lipid, ph osphatidylcholine, as compared with the other peptides. However, when phosp hatidylethanolamine replaced phosphatidylcholine, the lytic potency of PGLa and the alpha -helical model peptides was reduced, whereas that of (KIGAKI )(3)-NH2 was improved. Fluorescence experiments using analogs containing a single tryptophan residue showed significant differences between (KIGAKI)(3 )-NH2 and the alpha -helical peptides in their interactions with lipid vesi cles. Because the data suggest enhanced selectivity between bacterial and m ammalian lipids, linear amphipathic beta -sheet peptides such as (KIGAKI)3- NH2 warrant further investigation as potential antimicrobial agents.