How do Self-Assembling Antimicrobial Lipopeptides Kill Bacteria?
How do Self-Assembling Antimicrobial Lipopeptides Kill Bacteria?
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DOI：
10.1021/acsami.0c17222
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发表时间：
2020-12-16
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;Sani, Marc-Antoine;Lu, Jian Ren
抗菌肽是传统抗生素的有前景的替代品。一组自组装脂肽是通过将酰基链连接到具有序列 C-x-G(IIKK)(y)I-NH2 (C(x)G(y), x = 4-12 和 y = 2) 的 α-螺旋形成肽的 N 末端而形成的。 C(x)G(y) 在高于其临界聚集浓度 (CAC) 时自组装成纳米纤维。随着 x 的增加，CAC 减少，疏水相互作用增加，促进纳米纤维内二级结构的转变。由最小抑制浓度 (MIC) 决定的抗菌活性也随着 x 的增加而降低，但 MIC 明显小于 CAC，表明有效的细菌膜破坏能力。与传统抗生素不同，C(8)G(2) 和 C(12)G(2) 在研究浓度下仅接触几分钟后即可杀死金黄色葡萄球菌和大肠杆菌。 C(12)G(2) 纳米纤维比其非聚集单体具有更快的杀伤动力学和更低的细胞毒性。迄今为止，肽聚集体的抗菌活性尚未得到充分开发，人们发现它是一种非常有前途的肽设计机制。基于超分辨率荧光显微镜、固态核磁共振、原子力显微镜、中子散射/反射率、圆二色性和布鲁斯特角显微镜，提供了所涉及分子机制的详细证据。
Antimicrobial peptides are promising alternatives to traditional antibiotics. A group of self-assembling lipopeptides was formed by attaching an acyl chain to the N-terminus of alpha-helixforming peptides with the sequence C-x-G(IIKK)(y)I-NH2 (C(x)G(y), x = 4-12 and y = 2). C(x)G(y) self-assemble into nanofibers above their critical aggregation concentrations (CACs). With increasing x, the CACs decrease and the hydrophobic interactions increase, promoting secondary structure transitions within the nanofibers. Antimicrobial activity, determined by the minimum inhibition concentration (MIC), also decreases with increasing x, but the MICs are significantly smaller than the CACs, suggesting effective bacterial membrane-disrupting power. Unlike conventional antibiotics, both C(8)G(2) and C(12)G(2) can kill Staphylococcus aureus and Escherichia coli after only minutes of exposure under the concentrations studied. C(12)G(2) nanofibers have considerably faster killing dynamics and lower cytotoxicity than their nonaggregated monomers. Antimicrobial activity of peptide aggregates has, to date, been underexploited, and it is found to be a very promising mechanism for peptide design. Detailed evidence for the molecular mechanisms involved is provided, based on superresolution fluorescence microscopy, solid-state nuclear magnetic resonance, atomic force microscopy, neutron scattering/reflectivity, circular dichroism, and Brewster angle microscopy.