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首页> 外文期刊>Biochemistry >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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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

机译：MSI-78，MSI-367，MSI-594和MSI-843抗菌肽对洗涤剂类型的膜片段化作用和胆固醇的抑制作用：固态核磁共振研究

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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.
机译：对现有抗生素的多药耐药性正在成为全球性的威胁，可以使用阳离子抗菌肽（AMP）设计的任何潜在药物都可以作为缓解该现有问题的替代解决方案。与小分子抗生素相比，AMP杀死细菌的作用机理有很大的不同。 AMP的主​​要目标是与细胞膜的脂双层相互作用并破坏它以杀死细菌。因此，导致AMP选择性的膜相互作用模式非常重要。在这里，我们使用了不同的膜成分，例如带负电荷的，两性离子的或混合的大单层囊泡（LUV），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，取决于MSI肽的氨基酸序列和/或LUV的膜组成，MSI肽通过类似洗涤剂的地毯机制将LUV片段化。有趣的是，碎片化的脂质聚集体（例如SUV或胶束）足够小，无法在3113 NMR光谱中产生各向同性的峰。这些碎片化的脂质聚集体仅包含赋予脂质分子的MSI肽，如NMR和圆二色光谱法所证实的那样。我们的研究结果还表明，仅存在于真核细胞膜中的胆固醇会抑制MSI诱导的LUV片段化，表明MSI肽可以区分细菌和真核细胞膜，这种选择性可用于进一步开发新型抗生素。

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