细菌细胞死亡：原子级模拟揭示结构纳米工程星形肽聚合物的成孔作用模式
Bacterial cell death: Atomistic simulations reveal pore formation as a mode of action of structurally nano engineered star peptide polymers
AI总结：
本文通过原子级分子动力学模拟揭示了交替嵌段和随机SNAPPs与脂质双层相互作用并导致成孔形成、进而引起细菌细胞死亡的逐步分子机制，为优化SNAPPs结构以对抗多重耐药菌提供了基础。
摘要：
对常规抗生素的多重耐药性（MDR）是当前最紧迫的全球健康威胁之一，因此亟需开发有效、生物相容性好且不易诱发耐药性的抗菌剂。结构纳米工程抗菌肽聚合物（SNAPPs）是一类新颖且有前景的替代方案。这些星形聚合物由一个树枝状核心和多条由不同氨基酸序列共肽组成的臂构成。通过一系列全面的体内实验，我们（Nature Microbiology, 1, 16162, 2016）证明，臂由赖氨酸（K）和缬氨酸（V）残基随机嵌段组成的SNAPPs对所测试的革兰氏阴性和革兰氏阳性细菌均表现出亚微摩尔级的M效力。冷冻透射电子显微镜（Cryo-TEM）图像表明，具有随机嵌段共肽臂的SNAPP通过成孔作用作为其作用模式之一。然而，导致SNAPP这种作用模式的分子机制尚未被完全理解。为弥补这一空白，我们采用原子级分子动力学模拟技术，研究了三种不同氨基酸序列，即1）交替嵌段KKV、2）随机嵌段和3）双嵌段基序，对其臂的二级结构、SNAPP整体构型以及它们与脂质双层相互作用的影响。我们首次鉴定出交替嵌段和随机SNAPPs与脂质双层相互作用并导致成孔形成、进而引起细胞死亡的逐步机制。这些见解为进一步优化SNAPPs的化学结构以实现对MDR细菌的最大效能奠定了坚实基础，从而为应对抗生素耐药性和开发有效抗菌剂提供了一条有前景的途径。
英文摘要：
Multidrug resistance (MDR) to conventional antibiotics is one of the most urgent global health threats, necessitating the development of effective and biocompatible antimicrobial agents that are less inclined to provoke resistance. Structurally Nanoengineered Antimicrobial Peptide Polymers (SNAPPs) are a novel and promising class of such alternatives. These star-shaped polymers are made of a dendritic core with multiple arms made of co-peptides with varying amino acid sequences. Through a comprehensive set of in vivo experiments, we (Nature Microbiology, 1, 16162, 2016) showed that SNAPPs with arms made of random blocks of lysine (K) and valine (V) residues exhibit sub-micron M efficacy against Gram-negative and Gram-positive bacteria tested. Cryo-TEM images suggested pore formation by SNAPP with random block co-peptide arms as one of their mode of actions. However, the molecular mechanisms responsible for this mode of action of SNAPP were not fully understood. To address this gap, we employed atomistic molecular dynamics simulation technique to investigate the influence of three different sequences of amino acids, namely 1) alternating block KKV 2) random block and 3) di-block motifs on secondary structure of their arms and SNAPP's overall configuration as well as their interactions with lipid bilayer. We, for the first time identified a step-by-step mechanism through which alternating block and random SNAPPs interact with lipid bilayer and leads to pore formation, hence cell death. These insights provide a strong foundation for further optimization of the chemical structure of SNAPPs for maximum performance against MDR bacteria, therefore offering a promising avenue for addressing antibiotic resistance and development of effective antibacterial agents.
机构、总结、中文摘要均由AI分析而来，可能存在错误，请以论文正文为准。
