Daptomycin Strongly Affects the Phase Behavior of Model Lipid Bilayers
Daptomycin Strongly Affects the Phase Behavior of Model Lipid Bilayers
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DOI：
10.1021/acs.jpcb.0c06640
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发表时间：
2020-10-01
影响因子：
3.3
通讯作者：
Alessandrini, Andrea
中科院分区：
文献类型：
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作者：
Mescola, Andrea;Ragazzini, Gregorio;Alessandrini, Andrea
达托霉素 (DAP) 是一种钙依赖性环状脂肽，对带有磷脂酰甘油 (PG) 头基的带负电荷的磷脂具有很强的亲和力，自 2003 年以来一直被用作治疗革兰氏阳性菌引起的严重感染的最后手段抗生素。其作用机制的第一步涉及与细菌膜的相互作用，细菌膜不仅代表物理屏障，还容纳跨膜蛋白，如受体、转运蛋白和酶，其活性对细菌的生存至关重要。与激活或抑制与特定靶蛋白相关的生化途径的普通抗生素相比，这导致病原体制定耐药策略的效率较低。尽管已经上市，DAP 的分子作用机制仍然是一个有争议的研究课题，它很可能是多种不同作用综合作用的结果。了解 DAP 如何靶向病原体的膜对于寻找能够更好地避免耐药性产生的类似物有很大帮助。在这里，利用荧光显微镜和原子力显微镜（AFM），我们证明了 DAP 影响含有 PG 部分的脂质混合物的热力学行为。无论PG脂质是处于液相还是固相，DAP优选地与该头基相互作用并且能够更深入地渗透到存在该头基的区域中的脂质双层中。特别是，考虑到 AFM/光谱研究的结果，DAP 似乎对 PG 脂质主要处于液相的区域产生硬化效应，而它导致 PG 脂质处于固相的区域流化。
Daptomycin (DAP) is a calcium-dependent cyclic lipopeptide with great affinity for negatively charged phospholipids bearing the phosphatidylglycerol (PG) headgroup and has been used since 2003 as a last resort antibiotic in the treatment of severe infections caused by Gram-positive bacteria. The first step of its mechanism of action involves the interaction with the bacterial membrane, which not only represents a physical barrier but also accommodates transmembrane proteins, such as receptors, transporters, and enzymes, whose activity is crucial for the survival of bacteria. This results in a less efficient development of resistance strategies by pathogens compared to common antibiotics that activate or inhibit biochemical pathways connected to specific target proteins. Although already on the market, the molecular mechanism of action of DAP is still a controversial subject of investigation and it is most likely the result of a combination of distinct effects. Understanding how DAP targets the membrane of pathogens could be of great help in finding its analogues that could better avoid the development of resistance. Here, exploiting fluorescence microscopy and atomic force microscopy (AFM), we demonstrated that DAP affects the thermodynamic behavior of lipid mixtures containing PG moieties. Regardless of whether the PG lipids are in the liquid or solid phase, DAP preferably interacts with this headgroup and is able to penetrate more deeply into the lipid bilayer in the regions where this headgroup is present. In particular, considering the results of an AFM/spectroscopy investigation, DAP appears to produce a stiffening effect of the domains where PG lipids are mainly in the fluid phase, whereas it causes fluidification of the domains where PG lipids are in the solid phase.