Institute of Bioengineering, Queen Mary University of London, Mile End Road, London, E1 4NS, UK.
School of Engineering & Materials Science, Queen Mary University of London, Mile End Road, London, E1 4NS, UK.
J Membr Biol. 2019 Oct;252(4-5):317-329. doi: 10.1007/s00232-019-00068-3. Epub 2019 May 16.
The resistance of pathogens to traditional antibiotics is currently a global issue of enormous concern. As the discovery and development of new antibiotics become increasingly challenging, synthetic antimicrobial lipopeptides (AMLPs) are now receiving renewed attention as a new class of antimicrobial agents. In contrast to traditional antibiotics, AMLPs act by physically disrupting the cell membrane (rather than targeting specific proteins), thus reducing the risk of inducing bacterial resistance. In this study, we use microsecond-timescale atomistic molecular dynamics simulations to quantify the interaction of a short AMLP (C16-KKK) with model bacterial lipid bilayers. In particular, we investigate how fundamental transmembrane properties change in relation to a range of lipopeptide concentrations. A number of structural, mechanical, and dynamical features are found to be significantly altered in a non-linear fashion. At 10 mol% concentration, lipopeptides have a condensing effect on bacterial bilayers, characterized by a decrease in the area per lipid and an increase in the bilayer order. Higher AMLP concentrations of 25 and 40 mol% destabilize the membrane by disrupting the bilayer core structure, inducing membrane thinning and water leakage. Important transmembrane properties such as the lateral pressure and dipole potential profiles are also affected. Potential implications on membrane function and associated proteins are discussed.
目前，病原体对抗生素的耐药性是一个备受全球关注的问题。由于新抗生素的发现和开发变得越来越具有挑战性，合成抗菌脂肽（AMLPs）作为一类新的抗菌剂重新引起了人们的关注。与传统抗生素不同，AMLPs 通过物理破坏细胞膜（而不是针对特定蛋白质）起作用，从而降低了诱导细菌耐药性的风险。在这项研究中，我们使用微秒时间尺度的原子分子动力学模拟来量化短脂肽（C16-KKK）与模型细菌脂质双层的相互作用。特别是，我们研究了在一系列脂肽浓度下，基本的跨膜性质如何发生变化。发现许多结构、力学和动力学特征以非线性方式发生显著变化。在 10 mol% 的浓度下，脂肽对细菌双层具有浓缩作用，表现为脂质面积减少和双层有序性增加。更高浓度的 25 和 40 mol% 的 AMLP 通过破坏双层核心结构使膜不稳定，导致膜变薄和水泄漏。侧向压力和偶极电位分布等重要的跨膜性质也受到影响。讨论了对膜功能和相关蛋白的潜在影响。
