Coarse-grained simulations uncover Gram-negative bacterial defense against polymyxins by the outer membrane.
Coarse-grained simulations uncover Gram-negative bacterial defense against polymyxins by the outer membrane.
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粗粒度模拟揭示了革兰氏阴性细菌通过外膜对多粘菌素的防御。
DOI：
10.1016/j.csbj.2021.06.051
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发表时间：
2021
影响因子：
6
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Jiang X;Sun Y;Yang K;Yuan B;Velkov T;Wang L;Li J
使用 Ra LPS 开发了细菌外膜 (OM) 的结构模型。揭示了多粘菌素与 OM 相互作用的自由能图谱。 LPS 核心糖和钙离子赋予抗生素内在的耐药性。革兰氏阴性菌的外膜（OM）是对抗抗生素的强大屏障。了解 OM 的结构和功能对于发现针对多重耐药革兰氏阴性病原体的新型膜作用剂至关重要。然而，利用晶体学方法获得细菌膜的三维结构仍然具有挑战性，这极大地阻碍了其与抗生素相互作用的阐明。在这里，我们开发了一个由粗脂多糖 (LPS) 和三种关键类型的磷脂组成的不对称 OM 模型。使用粗粒度分子动力学模拟，我们研究了含有 LPS 的 OM 与多粘菌素的相互作用动力学，多粘菌素是对抗革兰氏阴性“超级细菌”的最后一类抗生素。我们发现多粘菌素分子自发地穿透 OM 核心糖区，在进入脂质 A 区之前，大多数多粘菌素分子被捕获。对多粘菌素渗透的自由能曲线的检查揭示了 LPS 内核和脂质 A 界面处的主要自由能屏障。进一步分析显示钙离子主要分布在内核区域并介导LPS分子之间广泛的交联相互作用，从而抑制多粘菌素渗透到OM的疏水区域。总的来说，我们的结果为革兰氏阴性菌对多粘菌素的内在防御提供了新的机制见解，并可能有助于确定新的抗菌靶点。
A structural model of bacterial outer membrane (OM) was developed with Ra LPS. Free energy landscape was revealed for polymyxin interactions with the OM. LPS core sugars and calcium ions confer intrinsic resistance to antibiotics. The outer membrane (OM) of Gram-negative bacteria is a formidable barrier against antibiotics. Understanding the structure and function of the OM is essential for the discovery of novel membrane-acting agents against multidrug-resistant Gram-negative pathogens. However, it remains challenging to obtain three-dimensional structure of bacterial membranes using crystallographic approaches, which has significantly hindered the elucidation of its interaction with antibiotics. Here, we developed an asymmetric OM model consisting of rough lipopolysaccharide (LPS) and three key types of phospholipids. Using coarse-grained molecular dynamics simulations, we investigated the interaction dynamics of LPS-containing OM with the polymyxins, a last-line class of antibiotics against Gram-negative ‘superbugs’. We discovered that polymyxin molecules spontaneously penetrated the OM core sugar region where most were trapped before entering the lipid A region. Examination of the free energy profile of polymyxin penetration revealed a major free energy barrier at the LPS inner core and lipid A interface. Further analysis revealed calcium ions predominantly distributed in the inner core region and mediated extensive cross-linking interactions between LPS molecules, thereby inhibiting the penetration of polymyxins into the hydrophobic region of the OM. Collectively, our results provide novel mechanistic insights into an intrinsic defense of Gram-negative bacteria to polymyxins and may help identify new antimicrobial targets.
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影响因子：
21.1
作者：
Nang SC;Azad MAK;Velkov T;Zhou QT;Li J
通讯作者：
Li J
影响因子：
3.2
作者：
Loutet, SA;Flannagan, RS;Valvano, MA
通讯作者：
Valvano, MA
影响因子：
5.2
作者：
Jiang, Xukai;Yang, Kai;Li, Jian
通讯作者：
Li, Jian
影响因子：
3.4
作者：
Lopez, Cesar A.;Zgurskaya, Helen;Gnanakaran, S.
通讯作者：
Gnanakaran, S.
影响因子：
5.3
作者：
Jiang X;Yang K;Han ML;Yuan B;Li J;Gong B;Velkov T;Schreiber F;Wang L;Li J
通讯作者：
Li J