Shai Y, Oren Z
Department of Membrane Research and Biophysics, Weizmann Institute of Science, Rehovot, Israel.
J Biol Chem. 1996 Mar 29;271(13):7305-8. doi: 10.1074/jbc.271.13.7305.
An amphipathic alpha-helical structure is considered to be a prerequisite for the lytic activity of most short linear cytolytic polypeptides that act on both mammalian cells and bacteria. This structure allows them also to exert diverse pathological and pharmacological effects, presumably by mimicking protein components that are involved in membrane-related events. In this study D-amino acid-incorporated analogues (diastereomers) of the cytolysin pardaxin, which is active against mammalian cells and bacteria, were synthesized and structurally and functionally characterized. We demonstrate that the diastereomers do not retain the alpha-helical structure, which in turn abolishes their cytotoxic effects on mammalian cells. However, they retain a high antibacterial activity, which is expressed in a complete lysis of the bacteria, as revealed by negative staining electron microscopy. The disruption of the alpha-helical structure should prevent the diastereomer analogues from permeating the bacterial wall by forming transmembrane pores but rather by dissolving the membrane as a detergent. These findings open the way for a new strategy in developing a novel class of highly potent antibacterial polypeptides for the treatment of infectious diseases, due to the increasing resistance of bacteria to the available antibacterial drugs.
两亲性α-螺旋结构被认为是大多数作用于哺乳动物细胞和细菌的短线性溶细胞多肽具有溶细胞活性的先决条件。这种结构还使它们能够发挥多种病理和药理作用，大概是通过模拟参与膜相关事件的蛋白质成分来实现的。在本研究中，合成了对哺乳动物细胞和细菌具有活性的溶细胞素豹蟾鱼毒素掺入D-氨基酸的类似物（非对映异构体），并对其进行了结构和功能表征。我们证明，这些非对映异构体不保留α-螺旋结构，进而消除了它们对哺乳动物细胞的细胞毒性作用。然而，它们保留了较高的抗菌活性，如负染色电子显微镜所示，表现为细菌完全裂解。α-螺旋结构的破坏应会阻止非对映异构体类似物通过形成跨膜孔渗透细菌壁，而是像去污剂一样溶解膜。由于细菌对现有抗菌药物的耐药性不断增加，这些发现为开发一类新型高效抗菌多肽用于治疗传染病开辟了新策略。
