Impact of Self-Assembly Properties on Antibacterial Activity of Short Acyl-Lysine Oligomers

Abstract

ABSTRACT We investigated both the structural and functional consequences of modifying the hydrophobic, lipopeptide-mimetic oligo-acyl-lysine (OAK) N α -hexadecanoyl- l -lysyl- l -lysyl-aminododecanoyl- l -lysyl-amide (c 16 KKc 12 K) to its unsaturated analog hexadecenoyl-KKc 12 K [c 16(ω7) KKc 12 K]. Despite similar tendencies for self-assembly in solution (critical aggregation concentrations, ∼10 μM), the analogous OAKs displayed dissimilar antibacterial properties (e.g., bactericidal kinetics taking minutes versus hours). Diverse experimental evidence provided insight into these discrepancies: whereas c 16(ω7) KKc 12 K created wiry interconnected nanofiber networks, c 16 KKc 12 K formed both wider and stiffer fibers which displayed distinct binding properties to phospholipid membranes. Unsaturation also shifted their gel-to-liquid transition temperatures and altered their light-scattering properties, suggesting the disassembly of c 16(ω7) KKc 12 K in the presence of bacteria. Collectively, the data indicated that the higher efficiency in interfering with bacterial viability emanated from a wobbly packing imposed by a single double bond. This suggests that similar strategies might improve hydrophobic OAKs and related lipopeptide antibiotics.