Impact of self-assembly properties on antibacterial activity of short acyl-lysine oligomers

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 (c₁₆KKc₁₂K) to its unsaturated analog hexadecenoyl- KKc₁₂K [c_16(ω7)KKc₁₂K]. 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)KKc₁₂K created wiry interconnected nanofiber networks, c₁₆KKc₁₂K 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)KKc₁₂K 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.