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(alpha)-hexadecanoyl-l-lysyl-l-lysyl-aminododecanoyl-l-lysyl-amide (c(16)KKc(12)K) to its unsaturated analog hexadecenoyl-KKc(12)K [c(16(omega7))KKc(12)K]. Despite similar tendencies for self-assembly in solution (critical aggregation concentrations, approximately 10 muM), 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(omega7))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(omega7))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.
Sarig
Hadar
H
Laboratory of Antimicrobial Peptides Investigation (LAPI), Department of Biotechnology & Food Engineering, Technion, Haifa 32000, Israel.
Rotem
Shahar
S
Ziserman
Lior
L
Danino
Dganit
D
Mor
Amram
A
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology; D002152:Calorimetry, Differential Scanning; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006095:Gram-Positive Cocci / Q000187:drug effects; D006461:Hemolysis; D057927:Hydrophobic and Hydrophilic Interactions; D008239:Lysine / Q000031:analogs & derivatives / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D009842:Oligopeptides; D008239:Lysine