Glycine Substitution Reduces Antimicrobial Activity and Helical Stretch of diPGLa-H in Lipid Micelles.

With the rise in antibiotic resistance, antimicrobial peptides (AMPs) show promise for therapeutic development, but higher specificity is required. PGLa-H is a naturally occurring decapeptide, reported to have moderate antibacterial activity and low hemolytic activity, with its sequence being identical to that of the C-terminal fragment of highly selective AMP, PGLa. DiPGLa-H, a sequential tandem repeat of PGLa-H, and Kiadin, an analogue with a Val to Gly substitution at position 15, display improved in vitro bactericidal activity against both Gram-negative and Gram-positive pathogens, with generally low toxicity for human cells. Despite Gly being a more flexible residue, NMR structural studies showed little difference in structure and dynamics between the two peptides for the first 14 residues, with somewhat greater flexibility in the C-terminus of Kiadin resulting in a tighter structure of the peptide in the presence of sodium dodecyl sulfate micelles. AMPs found in organisms often exhibit minimal amino acid mutations, and such small differences in peptide conformation may be utilized to design more selective AMPs.