Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark.
J Med Chem. 2014 Apr 10;57(7):2864-73. doi: 10.1021/jm401335p. Epub 2014 Mar 20.
Infections with multidrug-resistant pathogens are an increasing concern for public health. Recently, subtypes of peptide-peptoid hybrids were demonstrated to display potent activity against multidrug-resistant Gram-negative bacteria. Here, structural variation of these antibacterial peptidomimetics was investigated as a tool for optimizing cell selectivity. A protocol based on dimeric building blocks allowed for efficient synthesis of an array of peptide-peptoid oligomers representing length variation as well as different backbone designs displaying chiral or achiral peptoid residues. Lack of α-chirality in the side chains of the peptoid residues proved to be correlated to reduced cytotoxicity. Furthermore, optimization of the length of these peptidomimetics with an alternating cationic-hydrophobic design was a powerful tool to enhance the selectivity against Gram-negative pathogens over benign mammalian cells. Thus, lead compounds with a high selectivity toward killing of clinically important multidrug-resistant E. coli were identified.
多重耐药病原体感染对公共卫生越来越构成关注。最近，研究表明肽-聚肽混合的亚型对多种抗药性革兰氏阴性菌具有强大的活性。在这里，作为优化细胞选择性的工具，研究了这些抗菌肽模拟物的结构变化。基于二聚体构建块的方案允许高效合成一系列肽-聚肽寡聚物，这些寡聚物代表了长度变化以及不同的骨架设计，展示了手性或非手性聚肽残基。聚肽残基的侧链中缺乏α-手性被证明与降低细胞毒性相关。此外，通过交替的阳离子-疏水性设计优化这些肽模拟物的长度是增强对革兰氏阴性病原体相对于良性哺乳动物细胞的选择性的有力工具。因此，鉴定出了针对临床重要的多重耐药大肠杆菌具有高选择性的先导化合物。
