Structural Disruptions of the Outer Membranes of Gram-Negative Bacteria by Rationally Designed Amphiphilic Antimicrobial Peptides
Structural Disruptions of the Outer Membranes of Gram-Negative Bacteria by Rationally Designed Amphiphilic Antimicrobial Peptides
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DOI：
10.1021/acsami.1c01643
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发表时间：
2021-04-02
影响因子：
9.5
通讯作者：
Lu, Jian Ren
中科院分区：
文献类型：
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作者：
Gong, Haoning;Hu, Xuzhi;Lu, Jian Ren
革兰氏阴性菌被胞质内膜（IM）和外膜（OM）覆盖。抗菌肽（AMPs）必须首先通过OM和细胞壁渗透，然后攻击IM，引起细胞质渗漏并杀死细菌。细菌OM是一种不对称的双分子层，其外小叶主要由脂多糖（lps）组成，内小叶主要由磷脂（PLs）组成。针对革兰氏阴性菌，设计了两个阳离子α -螺旋AMPs，一个是全肽G(IIKK)(3)I-NH2 (G(3))，一个是疏水脂肽C-8-G(IIKK)(2)I-NH2 (C(8)G（2)，其中C(8)表示辛烷链）。脂多糖主导OM的功能，作为抵抗抗生素的第一道防线，从而降低药物敏感性。这项工作通过几个精心选择的OM模型探索了两种amp如何与LPS相互作用，这些模型促进了固态核磁共振（ss-NMR）、小角度中子散射（SANS）和中子反射率（NR）的测量。结果表明，G(3)分子较好地结合在LPS头部区域，并作为桥接分子将脱位的脂质重新组装成双层堆叠。相比之下，C(8)G(2)脂肽可以快速渗透到OM的中心区域，直接去除一些膜脂。不同的结构破坏暗示了这些amp的不同抗菌效果。OM对抗菌药物不同敏感性的结构特征的证明为未来开发菌株特异性抗菌药物提供了有用的途径。
Gram-negative bacteria are covered by both an inner cytoplasmic membrane (IM) and an outer membrane (OM). Antimicrobial peptides (AMPs) must first permeate through the OM and cell wall before attacking the IM to cause cytoplasmic leakage and kill the bacteria. The bacterial OM is an asymmetric bilayer with the outer leaflet primarily composed of lipopolysaccharides (LPSs) and the inner leaflet composed of phospholipids (PLs). Two cationic alpha-helical AMPs were designed to target Gram-negative bacteria, a full peptide G(IIKK)(3)I-NH2 (G(3)), and a hydrophobic lipopeptide C-8-G(IIKK)(2)I-NH2 (C(8)G(2), with C-8 denoting the octanoyl chain). LPS dominates OM functions as the first line of defense against antibiotics, thereby reducing drug susceptibility. This work explores how the two AMPs interact with LPS through several carefully chosen OM models that facilitated measurements from solid-state nuclear magnetic resonance (ss-NMR), small-angle neutron scattering (SANS), and neutron reflectivity (NR). The results revealed that G(3) molecules bound preferably to the LPS head region and functioned as bridge molecules to reassemble the dislocated lipids into bilayer stacks. In contrast, C(8)G(2) lipopeptides could quickly penetrate into the central region of the OM to cause direct removal of some membrane lipids. Different structural disruptions implicated different antimicrobial efficacies from these AMPs. The demonstration of the structural features underlying different susceptibilities of the OM to AMPs offers a useful route for the future development of strain-specific AMPs against antimicrobial-resistant pathogens.