外膜(OM)是革兰氏阴性细菌的一个标志性特征,它为该物种提供了对抗生素威胁的增强抵抗力,而阳离子抗菌肽(CAP)是天然抗生素,因其破坏细菌膜的能力而被广泛认可。众所周知,OM 上的脂多糖是 CAP 对抗革兰氏阴性菌活性的主要靶标之一。在这里,我们研究了带电残基沿初级肽序列的相对分布及其整体疏水性如何影响天然 CAP Ponericin W1 中的肽-OM 相互作用。使用源自 Ponericin W1 的设计肽库,我们确定,与 Lys 残基的构建体相比,在肽 N 或 C 末端连续放置 Lys 残基(例如“PonN”: KKKKKK WLGSALIGALLPSVVGLFQ)可增强肽与 OM 脂多糖的结合亲和力残基散布在整个一级序列中(例如“PonAmp”:WL KK AL K IGA K LLPSVV K LFKGSGQ)。同样发现,针对铜绿假单胞菌多重耐药菌株的抗菌活性在赖氨酸簇序列中最高。我们的研究结果表明,虽然天然 Ponericin W1 在 OM 处发挥其初始活性,但 Lys 聚类可能是增强该界面效力的一种有前途的方法,从而增强肽在 IM 处的进入和活性,对多重耐药物种具有明显的优势。
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Interaction of designed cationic antimicrobial peptides with the outer membrane of gram-negative bacteria
The outer membrane (OM) is a hallmark feature of gram-negative bacteria that provides the species with heightened resistance against antibiotic threats while cationic antimicrobial peptides (CAPs) are natural antibiotics broadly recognized for their ability to disrupt bacterial membranes. It has been well-established that lipopolysaccharides present on the OM are among major targets of CAP activity against gram-negative species. Here we investigate how the relative distribution of charged residues along the primary peptide sequence, in conjunction with its overall hydrophobicity, affects such peptide-OM interactions in the natural CAP Ponericin W1. Using a designed peptide library derived from Ponericin W1, we determined that the consecutive placement of Lys residues at the peptide N- or C-terminus (ex. “PonN”: KKKKKKWLGSALIGALLPSVVGLFQ) enhances peptide binding affinity to OM lipopolysaccharides compared to constructs where Lys residues are interspersed throughout the primary sequence (ex. “PonAmp”: WLKKALKIGAKLLPSVVKLFKGSGQ). Antimicrobial activity against multidrug resistant strains of Pseudomonas aeruginosa was similarly found to be highest among Lys-clustered sequences. Our findings suggest that while native Ponericin W1 exerts its initial activity at the OM, Lys-clustering may be a promising means to enhance potency towards this interface, thereby augmenting peptide entry and activity at the IM, with apparent advantage against multidrug-resistant species.