Lohner Karl
Institute of Molecular Biosciences, Biophysics Division, University of Graz, NAWI Graz, BioTechMed Graz, Humboldtstrasse 50/III, 8010 Graz, Austria.
Curr Top Med Chem. 2016 Jul 13.
The increase of pathogens being resistant to antibiotics represents a global health problem and thus, there is an urgent need for the development of antibiotics with novel mechanisms of action. Host defense peptides, which have direct antimicrobial activity (also termed antimicrobial peptides) or immune modulating activity, are valuable template structures for the development of such compounds. Antimicrobial peptides exhibit remarkably different structures as well as biological activity profiles with multiple targets. A large fraction of these peptides interfere physically with the cell membrane of bacteria (focus of this review), but can also translocate into the cytosol, where they interact with nucleic acids, ribosomes and proteins. Several potential interaction sites have to be considered on the route of the peptides from the environment to the cytoplasmic membrane. Translocation of peptides through the cell wall may not be impaired by the thick but relatively porous peptidoglycan layer. However, interaction with lipopolysaccharides of the outer membrane of Gram-negative bacteria and (lipo)teichoic acids of Gram-positive bacteria may reduce the effective concentration at the cytoplasmic membrane, where supposedly the killing event takes place. On a molecular level several mechanisms are discussed, which are important for the rational design of improved antimicrobial compounds: toroidal pore formation, carpet model (coverage of membrane surface by peptides), interfacial activity, void formation, clustering of lipids and effects of membrane curvature. In summary, many of these models just represent special cases that can be interrelated to each other and depend on the nature of lipids and peptides.
病原体对抗生素耐药性的增加是一个全球性的健康问题，因此，迫切需要开发具有新作用机制的抗生素。宿主防御肽具有直接抗菌活性（也称为抗菌肽）或免疫调节活性，是开发此类化合物的有价值的模板结构。抗菌肽表现出显著不同的结构以及针对多个靶点的生物活性谱。这些肽中的很大一部分会与细菌细胞膜发生物理相互作用（本综述的重点），但也可以转运到细胞质中，在那里它们与核酸、核糖体和蛋白质相互作用。在肽从环境到细胞质膜的途径中，必须考虑几个潜在的相互作用位点。肽通过细胞壁的转运可能不会受到厚但相对多孔的肽聚糖层的阻碍。然而，与革兰氏阴性菌外膜的脂多糖以及革兰氏阳性菌的（脂）磷壁酸相互作用可能会降低细胞质膜处的有效浓度，据推测杀伤事件发生在此处。在分子水平上讨论了几种机制，这些机制对于合理设计改进的抗菌化合物很重要：环形孔形成、地毯模型（肽覆盖膜表面）、界面活性、空洞形成、脂质聚集和膜曲率的影响。总之，这些模型中的许多仅仅代表了可以相互关联且取决于脂质和肽的性质的特殊情况。
