Center for Insoluble Protein Structures (inSPIN), Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Aarhus University, Langelandsgade 140, DK-8000 Aarhus C, Denmark.
J Phys Chem B. 2012 Jul 5;116(26):7652-9. doi: 10.1021/jp2098679. Epub 2012 Jun 25.
Bacterial resistance to classical antibiotics is a serious medical problem, which continues to grow. Small antimicrobial peptides represent a potential solution and are increasingly being developed as novel therapeutic agents. Many of these peptides owe their antibacterial activity to the formation of trans-membrane ion-channels resulting in cell lysis. However, to further develop the field of peptide antibiotics, a thorough understanding of their mechanism of action is needed. Alamethicin belongs to a class of peptides called peptaibols and represents one of these antimicrobial peptides. To examine the dynamics of assembly and to facilitate a thorough structural evaluation of the alamethicin ion-channels, we have applied click chemistry for the synthesis of templated alamethicin multimers covalently attached to cyclodextrin-scaffolds. Using oriented circular dichroism, calcein release assays, and single-channel current measurements, the α-helices of the templated multimers were demonstrated to insert into lipid bilayers forming highly efficient and remarkably stable ion-channels.
细菌对经典抗生素的耐药性是一个严重的医学问题，且耐药性持续增长。小抗菌肽代表了一种潜在的解决方案，越来越多地被开发为新型治疗药物。这些肽中的许多抗菌肽的活性归因于形成跨膜离子通道，导致细胞裂解。然而，为了进一步发展肽抗生素领域，需要深入了解其作用机制。短杆菌肽属于一类称为肽脂的肽，是这些抗菌肽之一。为了研究组装的动力学，并促进对短杆菌肽离子通道的彻底结构评估，我们应用点击化学合成了共价连接到环糊精支架上的模板化短杆菌肽多聚体。通过定向圆二色性、钙黄绿素释放实验和单通道电流测量，证明模板化多聚体的 α-螺旋插入脂质双层形成高效且非常稳定的离子通道。
