Molecular characterization of the outer membrane of Pseudomonas aeruginosa
Molecular characterization of the outer membrane of Pseudomonas aeruginosa
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DOI：
10.1016/j.bbamem.2019.183151
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发表时间：
2020-03-01
影响因子：
3.4
通讯作者：
Gnanakaran, S.
中科院分区：
文献类型：
--
作者：
Lopez, Cesar A.;Zgurskaya, Helen;Gnanakaran, S.
有效对抗革兰氏阴性菌的新抗生素的发现受到细菌双膜细胞包膜的低渗透性的阻碍。外膜（OM）是脂多糖（LPS）和磷脂的不对称双层，是有毒化合物的重要渗透屏障。OM的分子表征对于理解抗生素如何穿透这一屏障以及开发新的治疗策略和合理的药物设计至关重要。我们进行了全原子（AA）和粗粒（CG）分子动力学（MD）模拟，以表征铜绿假单胞菌，一种对大多数临床抗生素具有耐药性的人类病原体的完全组装的OM双层。这些模拟使用我们开发的AA和CG参数运行，以模拟铜绿假单胞菌的最丰富的LPS，特别是A带O-抗原。我们的模拟再现了几个实验确定的物理性质，如面积每脂质，膜刚度和增加的稳定性，由于与二价阳离子的相互作用。这些测试参数使我们能够研究各种OM特性，包括二价阳离子和OM电穿孔的影响。此外，大量和扩展的碳水化合物头部基团增加了水渗透，其朝向内瓣叶的脂肪族尾部传播。这种效应有助于内小叶中脂质的低有序化。此外，需要评估以了解外膜溶剂化的增加是否可以调节高极性药物的渗透。
Discovery of new antibiotics effective against Gram-negative bacteria is hampered by the low permeability of the bacterial two-membrane cell envelopes. The outer membrane (OM) is an asymmetric bilayer of lipopolysaccharides (LPS) and phospholipids and is a significant permeability barrier to noxious compounds. Molecular characterization of the OM is essential for understanding how antibiotics penetrate this barrier, and for the development of new therapeutic strategies and rational drug design. We carry out all-atom (AA) and coarse-grained (CG) molecular dynamics (MD) simulations to characterize the fully assembled OM bilayer of Pseudomonas aeruginosa, a human pathogen resistant to most clinical antibiotics. These simulations were run using AA and CG parameters that we developed to model the most abundant LPS of P. aeruginosa, specifically the A band O-antigen. Our simulations reproduce several experimentally determined physical properties such as area per lipid, membrane stiffness and increased stability due to the interaction with divalent cations. These tested parameters allowed us to study various OM properties including the effect of divalent cations and OM electroporation. In addition, the massive and extended carbohydrate head groups increase water permeation, which propagates towards the aliphatic tails of the inner leaflet. This effect contributes to the low ordering of the lipids in the inner leaflet. Further, evaluation is needed to understand whether the increased solvation of outer membrane could modulate permeation of highly polar drugs.