State Key Laboratory of Heavy Oil Processing and Centre for Bioengineering and Biotechnology, China University of Petroleum (East China), 66 Changjiang West Road, Qingdao 266580, China.
State Key Laboratory of Heavy Oil Processing and Centre for Bioengineering and Biotechnology, China University of Petroleum (East China), 66 Changjiang West Road, Qingdao 266580, China.
J Colloid Interface Sci. 2023 Nov;649:535-546. doi: 10.1016/j.jcis.2023.05.168. Epub 2023 Jun 2.
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.
脂肽已成为最有效的抗菌剂之一，然而，目前人们对于它们的物理化学性质和生物活性之间的联系还没有共识，特别是它们固有的聚集倾向和抗菌效力。为此，我们在此从头设计了一系列脂肽（CHO-(VVKK)V-NH），其中一个烷基链通过共价键连接到一个短阳离子肽序列的 N 端，该序列具有疏水性 VV（缬氨酸）和带正电荷 KK（赖氨酸）基序的交替模式。通过改变烷基链的长度（正辛酸（C8）、月桂酸（C12）和棕榈酸（C16）），脂肽表现出不同的物理化学性质和自组装行为，这对其抗菌活性有很大影响。CHO-(VVKK)V-NH 具有最低的疏水性和表面活性，抗菌活性最低。CHO-(VVKK)V-NH 和 CHO-(VVKK)V-NH 都具有较高的疏水性和表面活性，并自组装成长纳米纤维。然而，CHO-(VVKK)V-NH 形成的纳米纤维通过稀释而解组装，导致其通过破坏细菌膜而具有高抗菌活性。相比之下，CHO-(VVKK)V-NH 形成的纳米纤维非常稳定，可以紧密附着在细菌表面但不能穿透细菌膜，导致其抗菌活性低。因此，除了脂肽纳米结构的形态外，稳定性也有助于其抗菌能力。重要的是，这项研究增强了我们对自组装脂肽抗菌机制的理解，这将有助于探索其在生物医学中的应用。
