Detergent-Type Membrane Fragmentation by MSI-78, MSI-367, MSI-594, and MSI-843 Antimicrobial Peptides and Inhibition by Cholesterol: A Solid-State Nuclear Magnetic Resonance Study
Detergent-Type Membrane Fragmentation by MSI-78, MSI-367, MSI-594, and MSI-843 Antimicrobial Peptides and Inhibition by Cholesterol: A Solid-State Nuclear Magnetic Resonance Study
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DOI：
10.1021/bi501418m
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发表时间：
2015-03-17
期刊：
影响因子：
2.9
通讯作者：
Ramamoorthy, Ayyalusamy
中科院分区：
文献类型：
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作者：
Lee, Dong-Kuk;Bhunia, Anirban;Ramamoorthy, Ayyalusamy
对现有抗生素的多药耐药正在成为一个全球性的威胁，任何使用阳离子抗菌肽（AMP）设计的潜在药物都可能是缓解这一现有问题的替代解决方案。与小分子抗生素相比，AMP杀灭细菌的作用机制有很大不同。amp的主要目标是与细胞膜的脂质双分子层相互作用并破坏它以杀死细菌。因此，了解导致AMP选择性的膜相互作用模式是非常重要的。在这里，我们使用不同的膜组成，如带负电荷、两性离子或混合大单层囊泡（LUVs），来研究四种不同的合成设计的阳离子线性抗菌肽的相互作用：MSI-78（商业上称为pexiganan）、MSI-367、MSI-594和MSI-843。我们的固态核磁共振（NMR）实验证实，根据MSI肽的氨基酸序列和/或luv的膜组成，MSI肽通过一种类似洗涤剂的地毯机制使luv破碎。有趣的是，碎片状的脂质聚集体（如suv或胶束）足够小，可以在3113核磁共振光谱中产生各向同性峰。这些碎片状的脂质聚集体仅含有具有脂质分子的MSI肽，经核磁共振和圆二色光谱证实。我们的研究结果还表明，仅存在于真核细胞膜上的胆固醇抑制了MSI诱导的luv断裂，这表明MSI肽可以区分细菌和真核细胞膜，这种选择性可以用于进一步开发新型抗生素。
Multidrug resistance against the existing antibiotics is becoming a global threat, and any potential drug that can be designed using cationic antimicrobial peptides (AMP) could be an alternate solution to alleviate this existing problem. The mechanism of action of killing bacteria by an AMP differs drastically in comparison to that of small molecule antibiotics. The main target of AMPs is to interact with the lipid bilayer of the cell membrane and disrupt it to kill bacteria. Consequently, the modes of membrane interaction that lead to the selectivity of an AMP are very important to understand. Here, we have used different membrane compositions, such as negatively charged, zwitterionic, or mixed large unilamellar vesicles (LUVs), to study the interaction of four different synthetically designed cationic, linear antimicrobial peptides: MSI-78 (commercially known as pexiganan), MSI-367, MSI-594, and MSI-843. Our solid-state nuclear magnetic resonance (NMR) experiments confirmed that the MSI peptides fragmented LUVs through a detergent-like carpet mechanism depending on the amino acid sequence of the MSI peptide and/or the membrane composition of LUVs. Interestingly, the fragmented lipid aggregates such as SUVs or micelles are sufficiently small to produce an isotropic peak in the 3113 NMR spectrum. These fragmented lipid aggregates contain only MSI peptides bestowed with lipid molecules as confirmed by NMR in conjunction with circular dichroism spectroscopy. Our results also demonstrate that cholesterol, which is present only in the eukaryotic cell membrane, inhibits the MSI-induced fragmentation of LUVs, suggesting that the MSI peptides can discriminate the bacteria and the eukaryotic cell membranes, and this selectivity could be used for further development of novel antibiotics.