Mechanism of a prototypical synthetic membrane-active antimicrobial: Efficient hole-punching via interaction with negative intrinsic curvature lipids
Mechanism of a prototypical synthetic membrane-active antimicrobial: Efficient hole-punching via interaction with negative intrinsic curvature lipids
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DOI：
10.1073/pnas.0806456105
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发表时间：
2008-12-30
影响因子：
11.1
通讯作者：
Wong, Gerard C. L.
中科院分区：
文献类型：
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作者：
Yang, Lihua;Gordon, Vernita D.;Wong, Gerard C. L.
亚苯基乙炔基包含一类典型的合成抗菌化合物，其模拟真核生物产生的抗菌肽并具有广谱抗菌活性。我们明确表明，这些抗菌剂对细菌膜的渗透取决于负固有曲率脂质的存在，例如细菌膜内高浓度的磷脂酰乙醇胺（PE）脂质。平板杀灭试验表明，针对膜活性苯乙炔类抗菌剂，PE 敲除突变型大肠杆菌的存活率远远超过野生型，而当受到传统代谢抗生素的挑战时，情况恰恰相反。 PE缺失在正常环境中是一种致命突变，这表明耐药菌株不会进化，因为需要致命突变才能获得免疫力。 PE脂质可以有效地产生诱导膜孔的圆周桶所需的负曲率；由少量的抗菌分子诱导形成由水通道阵列组成的倒六边形 H-II 相。这些水通道中估计的抗菌剂占据是非线性的，并且随着总体抗菌剂浓度的增加，从每 4 nm 诱导水通道长度大约 1 跃升至 3 个。通过与磁性系统的精确可解一维自旋模型进行比较，我们量化了这些抗菌剂的协同作用。
Phenylene ethynylenes comprise a prototypical class of synthetic antimicrobial compounds that mimic antimicrobial peptides produced by eukaryotes and have broad-spectrum antimicrobial activity. We show unambiguously that bacterial membrane permeation by these antimicrobials depends on the presence of negative intrinsic curvature lipids, such as phosphatidylethanolamine ( PE) lipids, found in high concentrations within bacterial membranes. Plate-killing assays indicate that a PE-knockout mutant strain of Escherichia coli drastically out-survives the wild type against the membrane-active phenylene ethynylene antimicrobials, whereas the opposite is true when challenged with traditional metabolic antibiotics. That the PE deletion is a lethal mutation in normative environments suggests that resistant bacterial strains do not evolve because a lethal mutation is required to gain immunity. PE lipids allow efficient generation of negative curvature required for the circumferential barrel of an induced membrane pore; an inverted hexagonal H-II phase, which consists of arrays of water channels, is induced by a small number of antimicrobial molecules. The estimated antimicrobial occupation in these water channels is nonlinear and jumps from approximate to 1 to 3 per 4 nm of induced water channel length as the global antimicrobial concentration is increased. By comparing to exactly solvable 1D spin models for magnetic systems, we quantify the cooperativity of these antimicrobials.