Molecular dynamics simulations informed by membrane lipidomics reveal the structure-interaction relationship of polymyxins with the lipid A-based outer membrane of Acinetobacter baumannii
Molecular dynamics simulations informed by membrane lipidomics reveal the structure-interaction relationship of polymyxins with the lipid A-based outer membrane of Acinetobacter baumannii
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DOI：
10.1093/jac/dkaa376
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发表时间：
2020-12-01
影响因子：
5.2
通讯作者：
Li, Jian
中科院分区：
文献类型：
--
作者：
Jiang, Xukai;Yang, Kai;Li, Jian
背景：耐多药细菌对全球人类健康构成紧迫威胁。多粘菌素是对抗危及生命的革兰氏阴性“超级细菌”的最后一线疗法，包括鲍曼不动杆菌。多粘菌素主要通过渗透细菌外膜（OM）发挥抗菌活性；然而，多粘菌素与OM在原子水平上的相互作用机制尚不清楚。方法：利用定量膜脂组学数据构建鲍曼不动杆菌的脂质OM模型，并采用伞式采样技术进行全原子分子动力学模拟，阐明多粘菌素[B-1和E-1（即粘菌素a）代表两种临床使用的多粘菌素]渗透OM的结构-相互作用关系和热力学。结果：多粘菌素B-1和粘菌素A通过多粘菌素的Dab残基与脂质A的磷酸之间的初始静电相互作用结合到鲍曼不动杆菌OM上，竞争性地取代OM头基团区域的阳离子。多粘菌素B-1和粘菌素A在接近OM疏水中心时形成独特的折叠构象，与先前的实验观察一致。多粘菌素的渗透诱导了OM脂质头部基团在渗透部位附近的重新定向，引起了局部膜的破坏，从而显著增加了膜的通透性，促进了多粘菌素分子随后渗透到OM和质周空间。结论：研究了多粘菌素通过鲍曼单胞菌外叶渗透的热力学规律，并在原子和膜水平上获得了新的结构-相互作用关系信息。我们的发现将有助于发现抗耐多药革兰氏阴性病原体的新型多粘菌素。
Background: MDR bacteria represent an urgent threat to human health globally. Polymyxins are a Last-Line therapy against Life-threatening Gram-negative 'superbugs', including Acinetobacter baumannii. Polymyxins exert antimicrobial activity primarily via permeabilizing the bacterial outer membrane (OM); however, the mechanism of interaction between polymyxins and the OM remains unclear at the atomic Level.Methods: We constructed a Lipid A-based OM model of A. baumannii using quantitative membrane Lipidomics data and employed all-atom molecular dynamics simulations with umbrella sampling techniques to elucidate the structure-interaction relationship and thermodynamics governing the penetration of polymyxins [B-1 and E-1 (i.e. colistin A) representing the two clinically used polymyxins] into the OM.Results: Polymyxin B-1 and colistin A bound to the A. baumannii OM by the initial electrostatic interactions between the Dab residues of polymyxins and the phosphates of Lipid A, competitively displacing the cations from the headgroup region of the OM. Both polymyxin B-1 and colistin A formed a unique folded conformation upon approaching the hydrophobic centre of the OM, consistent with previous experimental observations. Polymyxin penetration induced reorientation of the headgroups of the OM Lipids near the penetration site and caused Local membrane disorganization, thereby significantly increasing membrane permeability and promoting the subsequent penetration of polymyxin molecules into the OM and periplasmic space.Conclusions: The thermodynamics governing the penetration of polymyxins through the outer Leaflet of the A. baumannii OM were examined and novel structure-interaction relationship information was obtained at the atomic and membrane Level. Our findings will facilitate the discovery of novel polymyxins against MDR Gramnegative pathogens.