Dennison Sarah R, Morton Leslie Hg, Badiani Kamal, Harris Frederick, Phoenix David A
School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK.
Pepceuticals Limited, 4 Feldspar Close, Warrens Park, Enderby, Leicestershire, LE19 4JS, UK.
Soft Matter. 2023 Nov 1;19(42):8247-8263. doi: 10.1039/d3sm01007d.
Modelin-5 (M5-NH) killed with a minimum lethal concentration (MLC) of 5.86 μM and strongly bound its cytoplasmic membrane (CM) with a of 23.5 μM. The peptide adopted high levels of amphiphilic α-helical structure (75.0%) and penetrated the CM hydrophobic core (8.0 mN m). This insertion destabilised CM structure increased lipid packing and decreased fluidity (Δ < 0), which promoted high levels of lysis (84.1%) and cell death. M5-NH showed a very strong affinity ( = 3.5 μM) and very high levels of amphiphilic α-helical structure with cardiolipin membranes (96.0%,) which primarily drove the peptide's membranolytic action against . In contrast, M5-NH killed with an MLC of 147.6 μM and weakly bound its CM with a of 117.6 μM, The peptide adopted low levels of amphiphilic α-helical structure (35.0%) and only penetrated the upper regions of the CM (3.3 mN m). This insertion stabilised CM structure decreased lipid packing and increased fluidity (Δ > 0) and promoted only low levels of lysis (24.3%). The insertion and lysis of the CM by M5-NH showed a strong negative correlation with its lysyl phosphatidylglycerol (Lys-PG) content ( > 0.98). In combination, these data suggested that Lys-PG mediated mechanisms inhibited the membranolytic action of M5-NH against , thereby rendering the organism resistant to the peptide. These results are discussed in relation to structure/function relationships of M5-NH and CM lipids that underpin bacterial susceptibility and resistance to the peptide.
Modelin-5（M5-NH）的最低致死浓度（MLC）为5.86 μM ，可杀死细菌，并且以23.5 μM的解离常数与细胞质膜（CM）紧密结合。该肽具有高水平的两亲性α-螺旋结构（75.0%），并能穿透细胞质膜的疏水核心（8.0 mN m）。这种插入破坏了细胞质膜结构，增加了脂质堆积并降低了流动性（Δ<0），从而导致高水平裂解（84.1%）和细胞死亡。M5-NH对心磷脂膜表现出非常强的亲和力（解离常数=3.5 μM）以及非常高水平的两亲性α-螺旋结构（96.0%），这主要驱动了该肽对心磷脂膜的溶膜作用。相比之下，M5-NH杀死细菌的MLC为147.6 μM ，并以117.6 μM的解离常数与细胞质膜弱结合，该肽具有低水平的两亲性α-螺旋结构（35.0%），仅能穿透细胞质膜的上层区域（3.3 mN m）。这种插入稳定了细胞质膜结构，减少了脂质堆积并增加了流动性（Δ>0），仅促进了低水平的裂解（24.3%）。M5-NH对细胞质膜的插入和裂解与其赖氨酰磷脂酰甘油（Lys-PG）含量呈强负相关（相关系数>0.98）。综合来看，这些数据表明Lys-PG介导的机制抑制了M5-NH对细菌细胞质膜的溶膜作用，从而使该生物体对该肽产生抗性。本文结合M5-NH与细胞质膜脂质的结构/功能关系对这些结果进行了讨论，这些关系是细菌对该肽敏感性和抗性的基础。
