Disassembling ability of lipopeptide promotes the antibacterial activity.

Lipopeptides have become one of the most potent antibacterial agents, however, there is so far no consensus about the link between their physic-chemical properties and biological activity, in particular their inherent aggregation propensity and antibacterial potency. To this end, we here de novo design a series of lipopeptides (CHO-(VVKK)V-NH), in which an alkyl chain is covalently attached onto the N-terminus of a short cationic peptide sequence with an alternating pattern of hydrophobic VV (Val) and positively charged KK (Lys) motifs. By varying the alkyl chain length (ortho-octanoic acid (C8), lauric acid (C12), and palmitic acid (C16)), the lipopeptides show distinct physicochemical properties and self-assembly behaviors, which have great effect on their antibacterial activities. CHO-(VVKK)V-NH, which contains the lowest hydrophobicity and surface activity has the lowest antibacterial activity. CHO-(VVKK)V-NH and CHO-(VVKK)V-NH both have high hydrophobicity and surface activity, and self-assembled into long nanofibers. However, the nanofibers formed by CHO-(VVKK)V-NH disassembled by dilution, resulting in its high antibacterial activity via bacterial membrane disruption. Comparatively, the nanofibers formed by CHO-(VVKK)V-NH were very stable, which can closely attach on bacterial surface but not permeate bacterial membrane, leading to its low antibacterial activity. Thus, the stability other than the morphologies of lipopeptides' nanostructures contribute to their antibacterial ability. Importantly, this study enhances our understanding of the antibacterial mechanisms of self-assembling lipopeptides that will be helpful in exploring their biomedical applications.