The octapeptins are lipopeptide antibiotics that are structurally similar to polymyxins yet retain activity against polymyxin-resistant Gram-negative pathogens, suggesting they might be used to treat recalcitrant infections. However, the basis of their unique activity is unclear because of the difficulty in generating high-resolution experimental data of the interaction of antimicrobial peptides with lipid membranes. To elucidate these structure–activity relationships, we employed all-atom molecular dynamics simulations with umbrella sampling to investigate the conformational and energetic landscape of octapeptins interacting with bacterial outer membrane (OM). Specifically, we examined the interaction of octapeptin C4 and FADDI-115, lacking a single hydroxyl group compared with octapeptin C4, with the lipid A–phosphoethanolamine modified OM of Acinetobacter baumannii. Octapeptin C4 and FADDI-115 both penetrated into the OM hydrophobic center but experienced different conformational transitions from an unfolded to a folded state that was highly dependent on the structural flexibility of their respective N-terminal fatty acyl groups. The additional hydroxyl group present in the fatty acyl group of octapeptin C4 resulted in the molecule becoming trapped in a semifolded state, leading to a higher free energy barrier for OM penetration. The free energy barrier for the translocation through the OM hydrophobic layer was ∼72 kcal/mol for octapeptin C4 and 62 kcal/mol for FADDI-115. Our results help to explain the lower antimicrobial activity previously observed for octapeptin C4 compared with FADDI-115 and more broadly improve our understanding of the structure–function relationships of octapeptins. These findings may facilitate the discovery of next-generation octapeptins against polymyxin-resistant Gram-negative 'superbugs.'

中文翻译：

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八肽素-外膜相互作用的模拟表明构象灵活性与抗菌效力有关。

八肽素是脂肽类抗生素，在结构上与多粘菌素相似，但仍保留对耐多粘菌素的革兰氏阴性病原体的活性，表明它们可用于治疗顽固性感染。然而，由于难以产生抗菌肽与脂质膜相互作用的高分辨率实验数据，因此它们独特活性的基础尚不清楚。为了阐明这些结构-活性关系，我们采用全原子分子动力学模拟和伞状采样来研究八肽素与细菌外膜（OM）相互作用的构象和能量景观。具体来说，我们检查了八肽素 C4 和 FADDI-115 的相互作用，与八肽素 C4 相比，缺少单个羟基，用脂质 A-磷酸乙醇胺修饰鲍曼不动杆菌的 OM。Octapeptin C4 和 FADDI-115 都渗透到 OM 疏水中心，但经历了从未折叠状态到折叠状态的不同构象转变，这高度依赖于其各自 N 端脂肪酰基的结构灵活性。八肽肽 C4 的脂肪酰基中存在的额外羟基导致分子陷入半折叠状态，从而导致更高的 OM 渗透自由能垒。对于八肽肽 C4 和 FADDI-115，通过 OM 疏水层易位的自由能垒为 ~72 kcal/mol 和 62 kcal/mol。我们的结果有助于解释先前观察到的八肽肽 C4 与 FADDI-115 相比较低的抗菌活性，并更广泛地提高我们对八肽肽结构-功能关系的理解。这些发现可能有助于发现针对多粘菌素抗性革兰氏阴性“超级细菌”的下一代八肽素。