Department of Biochemistry and Biomedical Sciences, McMaster University Health Sciences Centre, Hamilton, Ontario L8N 3Z5, Canada.
Biochemistry. 2010 May 18;49(19):4076-84. doi: 10.1021/bi100378m.
Clustering of anionic lipids away from zwitterionic ones by cationic antimicrobial agents has recently been established as a mechanism of action of natural small, flexible peptides as well as non-natural synthetic peptide mimics. One of the largest classes of antimicrobial peptides consists of peptides that form cationic amphipathic helices on membranes and whose toxic action is dependent on the formation of pores in the membrane or through the "carpet" mechanism. We have evaluated the role of anionic lipid clustering for five of these peptides, i.e., MSI-78, MSI-103, MSI-469, MSI-843, and MSI-1254, with different sequences and properties. We determined whether these amphipathic helical cationic antimicrobial peptides cluster anionic lipids from zwitterionic ones and if this property is related to the species specificity of their toxicity. All five of these peptides were capable of lipid clustering, in contrast to the well-studied amphipathic helical antimicrobial peptide, magainin 2, which does not. We ascribe this difference to the lower density of positive charges in magainin 2. Peptides that efficiently cluster anionic lipids generally have a ratio of MIC for Staphylococcus aureus to that for Escherichia coli of >1. The addition of an N-terminal octyl chain did not preclude anionic charge clustering, although the ratio of MIC for S. aureus to that for E. coli was somewhat lowered. In most Gram-positive bacteria, there is a predominance of anionic lipids in the cytoplasmic membrane. In Gram-negative bacteria, however, clustering of anionic lipids away from zwitterionic ones is emerging as an important contributing mechanism of bacterial toxicity for some antimicrobial agents.
阳离子抗菌剂将阴离子脂质从两性离子脂质中排斥聚集，这一作用机制已被证实是天然小而灵活的肽类以及非天然合成肽模拟物发挥功效的原因之一。抗菌肽是最大的一类抗生素之一，其中包含在细胞膜上形成阳离子两亲性螺旋的肽类，其毒性作用依赖于在细胞膜上形成孔或通过“地毯”机制。我们评估了阴离子脂质排斥聚集在五类具有不同序列和性质的此类肽上的作用，即 MSI-78、MSI-103、MSI-469、MSI-843 和 MSI-1254。我们确定了这些两亲性螺旋阳离子抗菌肽是否将阴离子脂质从两性离子脂质中排斥聚集，以及这种特性是否与它们毒性的种属特异性有关。与研究透彻的两亲性螺旋抗菌肽，即抗菌肽 2 相反，所有这五种肽都能够进行脂质排斥聚集。我们将这种差异归因于抗菌肽 2 中带正电荷的密度较低。有效排斥聚集阴离子脂质的肽类，通常对金黄色葡萄球菌的最小抑菌浓度（MIC）与对大肠杆菌的 MIC 比值大于 1。尽管对金黄色葡萄球菌的 MIC 与对大肠杆菌的 MIC 比值略有降低，但添加 N 端辛基链并不能阻止阴离子电荷排斥聚集。在大多数革兰氏阳性菌的细胞质膜中，阴离子脂质占主导地位。然而，在革兰氏阴性菌中，阴离子脂质从两性离子脂质中排斥聚集正逐渐成为一些抗菌剂发挥细菌毒性的重要贡献机制。
