Daptomycin Strongly Affects the Phase Behavior of Model Lipid Bilayers.,The Journal of Physical Chemistry B

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Daptomycin Strongly Affects the Phase Behavior of Model Lipid Bilayers.
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2020-09-04 , DOI: 10.1021/acs.jpcb.0c06640
Andrea Mescola ₁ , Gregorio Ragazzini _{1,

2} , Andrea Alessandrini _{1,

2}

Affiliation

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.

中文翻译：

达托霉素强烈影响模型脂质双层的相行为。

达托霉素（DAP）是一种钙依赖性环脂肽，对带有磷脂酰甘油（PG）头基的带负电荷的磷脂具有极强的亲和力，自2003年以来一直用作治疗革兰氏阳性细菌引起的严重感染的最后手段。其作用机理的第一步涉及与细菌膜的相互作用，不仅代表物理屏障，而且还容纳跨膜蛋白，例如受体，转运蛋白和酶，其活性对细菌的生存至关重要。与激活或抑制连接到特定靶蛋白的生化途径的普通抗生素相比，病原体对耐药策略的开发效率较低。虽然已经在市场上，DAP作用的分子机制仍然是一个有争议的研究主题，并且很可能是多种不同作用结合的结果。了解DAP如何靶向病原体膜可能对找到可以更好避免耐药性发展的类似物有很大帮助。在这里，我们利用荧光显微镜和原子力显微镜（AFM），证明了DAP影响含有PG部分的脂质混合物的热力学行为。不管PG脂质是处于液相还是固相，DAP都优选与此头基相互作用，并能够更深地渗透到该头基存在的区域的脂质双层中。特别是考虑到原子力显微镜/光谱学调查的结果，

更新日期：2020-10-02

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