Mechanistic studies on the effect of membrane lipid acyl chain composition on daptomycin pore formation
Mechanistic studies on the effect of membrane lipid acyl chain composition on daptomycin pore formation
复制标题
膜脂酰基链组成对达托霉素孔形成影响的机理研究
DOI：
10.1016/j.chemphyslip.2018.09.015
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发表时间：
2018-11-01
影响因子：
3.4
通讯作者：
Palmer, Michael
中科院分区：
文献类型：
--
作者：
Beriashvili, David;Taylor, Robert;Palmer, Michael
达托霉素是一种脂肽抗生素，可结合革兰氏阳性菌的细胞膜并使其透化。膜透化需要目标膜中的钙和磷脂酰甘油 (PG)，并且它与可能包含八个亚基的低聚物的形成相关，这些亚基均匀分布在两个膜小叶之间。在细菌细胞和模型膜中，膜磷脂的脂肪酰基组成的变化可以防止透化。我们使用脂质体研究了含有油酰基和其他脂肪酰基残基的磷脂对达托霉素活性的影响，并得到以下观察结果：（1）当油酸残基不仅是PG的一部分，而且还包括其他磷脂（PC或心磷脂）时，油酸残基会抑制透化。 (2) 当包含在对达托霉素敏感的脂质混合物中时，即使是 10% 的二油酰脂质 (DOPC) 也能强烈抑制透化作用。 (3) 脂肪酰残基的抑制作用与其链长的相关性似乎比与不饱和度的相关性更大。 (4) 在所有测试条件下，透化与八聚体形成同时发生，而在未透化的膜上观察到四聚体。总的来说，我们的研究结果进一步支持了八聚体确实是功能性跨膜孔的观点，并且脂肪酰基残基可以通过阻止四聚体跨两个膜小叶的排列来防止孔形成。
Daptomycin is a lipopeptide antibiotic that binds and permeabilizes the cell membranes of Gram-positive bacteria. Membrane permeabilization requires both calcium and phosphatidylglycerol (PG) in the target membrane, and it correlates with the formation of an oligomer that likely comprises eight subunits, which are evenly distributed between the two membrane leaflets. In both bacterial cells and model membranes, changes in the fatty acyl composition of the membrane phospholipids can prevent permeabilization. We here used liposomes to study the effect of phospholipids containing oleoyl and other fatty acyl residues on daptomycin activity, and made the following observations: (1) Oleic acid residues inhibited permeabilization when part not only of PG, but also of other phospholipids (PC or cardiolipin). (2) When included in an otherwise daptomycin-susceptible lipid mixture, even 10% of dioleoyl lipid (DOPC) can strongly inhibit permeabilization. (3) The inhibitory effect of fatty acyl residues appears to correlate more with their chain length than with unsaturation. (4) Under all conditions tested, permeabilization coincided with octamer formation, whereas tetramers were observed on membranes that were not permeabilized. Overall, our findings further support the notion that the octamer is indeed the functional transmembrane pore, and that fatty acyl residues may prevent pore formation by preventing the alignment of tetramers across the two membrane leaflets.