Sphingosine kills bacteria by binding to cardiolipin
Sphingosine kills bacteria by binding to cardiolipin
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鞘氨醇通过与心磷脂结合来杀死细菌
DOI：
10.1074/jbc.ra119.012325
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Gulbins E
中科院分区：
文献类型：
--
作者：
Verhaegh R;Becker KA;Edwards MJ;Gulbins E
鞘氨醇是一种长链狮身人面像碱基，已被证明对许多病原体具有杀菌活性，包括铜绿假单胞菌、金黄色葡萄球菌和大肠杆菌。我们以前已经证明，鞘氨醇存在于鼻、气管和支气管上皮细胞中，并构成抵抗细菌病原体的呼吸道防御的中心成分。在这里，使用各种脂质结合和细胞生物学分析，我们证明了暴露P。铜绿假单胞菌和S。金黄色细胞对鞘氨醇的反应非常迅速，即在几分钟内使细菌质膜通透，导致细菌细胞渗漏，失去三磷酸腺苷，并失去细菌代谢活性。这些变化迅速导致细菌死亡。从机理上，我们证明了鞘氨醇中的质子化NH2基团的存在是鞘氨醇杀菌活性所必需的。我们还发现，鞘氨醇的质子化NH2基团与细菌质膜中带高负电荷的脂类心磷脂结合。值得注意的是，这种结合是鞘氨醇杀死细菌所必需的，正如基因实验所揭示的那样。颜色：P。缺乏心磷脂合成酶的铜绿假单胞菌在体外和体内对鞘氨醇具有抵抗力。我们认为鞘氨醇与心磷脂的结合使心磷脂分子聚集在细菌的质膜上。这种聚集导致细菌质膜中形成凝胶状甚至晶状结构，从而促进质膜的快速通透和细菌细胞死亡。
Sphingosine is a long-chain sphingoid base that has been shown to have bactericidal activity against many pathogens, includingPseudomonas aeruginosa,Staphylococcus aureus,andEscherichia coli. We have previously demonstrated that sphingosine is present in nasal, tracheal, and bronchial epithelial cells and constitutes a central element of the defense of the airways against bacterial pathogens. Here, using assorted lipid-binding and cell biology assays, we demonstrate that exposingP. aeruginosaandS. aureuscells to sphingosine results in a very rapid,i.e.within minutes, permeabilization of the bacterial plasma membrane, resulting in leakiness of the bacterial cells, loss of ATP, and loss of bacterial metabolic activity. These alterations rapidly induced bacterial death. Mechanistically, we demonstrate that the presence of the protonated NH2group in sphingosine, which is an amino-alcohol, is required for sphingosine's bactericidal activity. We also show that the protonated NH2group of sphingosine binds to the highly negatively–charged lipid cardiolipin in bacterial plasma membranes. Of note, this binding was required for bacterial killing by sphingosine, as revealed by genetic experiments indicating thatE. coliorP. aeruginosastrains that lack cardiolipin synthase are resistant to sphingosine, bothin vitroandin vivo. We propose that binding of sphingosine to cardiolipin clusters cardiolipin molecules in the plasma membrane of bacteria. This clustering results in the formation of gel-like or even crystal-like structures in the bacterial plasma membrane and thereby promotes rapid permeabilization of the plasma membrane and bacterial cell death.
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