Polymyxin B Loosens Lipopolysaccharide Bilayer but Stiffens Phospholipid Bilayer
Polymyxin B Loosens Lipopolysaccharide Bilayer but Stiffens Phospholipid Bilayer
复制标题
多粘菌素 B 松弛脂多糖双层，但强化磷脂双层
DOI：
10.1016/j.bpj.2019.11.008
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发表时间：
2020-01-07
影响因子：
3.4
通讯作者：
Fang, Weihai
中科院分区：
文献类型：
--
作者：
Fu, Lei;Wan, Mingwei;Fang, Weihai
多重耐药革兰氏阴性细菌增加了现代各种严重疾病的患病率。多粘菌素被用作治疗感染的最后一线治疗选择。然而，多粘菌素的作用机制仍有争议。在这项工作中，我们采用粗粒度的分子动力学模拟来研究阳离子抗菌肽多粘菌素B （PmB）与细菌内外膜模型的相互作用机制。我们的研究结果表明，PmB的结合通过置换反离子扰乱了外膜，降低了脂多糖尾部的取向顺序，并产生了更多的脂多糖包装缺陷。在结合到细胞膜上后，与抗菌肽诱导细胞膜穿孔的传统杀伤机制不同，PmBs不会渗透细胞膜，而是通过填充脂质堆积缺陷，增加脂质尾部序和膜弯曲刚度，限制脂质扩散，使细胞膜变硬。PmBs还介导膜间接触和粘附。这些共同作用表明，PmBs通过对细胞进行灭菌来剥夺革兰氏阴性菌的生物活性。
Multidrug-resistant Gram-negative bacteria have increased the prevalence of a variety of serious diseases in modern times. Polymyxins are used as the last-line therapeutic options for the treatment of infections. However, the mechanism of action of polymyxins remains in dispute. In this work, we used a coarse-grained molecular dynamics simulation to investigate the mechanism of the cationic antimicrobial peptide polymyxin B (PmB) interacting with both the inner and outer membrane models of bacteria. Our results show that the binding of PmB disturbs the outer membrane by displacing the counterions, decreasing the orientation order of the lipopolysaccharide tail, and creating more lipopolysaccharide packing defects. Upon binding onto the inner membrane, in contrast to the traditional killing mechanism that antimicrobial peptides usually use to induce holes in the membrane, PmBs do not permeabilize the inner membrane but stiffen it by filling up the lipid packing defect, increasing the lipid tail order and the membrane bending rigidity as well as restricting the lipid diffusion. PmBs also mediate intermembrane contact and adhesion. These joint effects suggest that PmBs deprive the biological activity of Gram-negative bacteria by sterilizing the cell.