Department of Biochemistry and Biophysics, University of Pennsylvania, 1010 Stellar Chance Laboratories, 422 Curie Blvd, Philadelphia, Pennsylvania 19104-4860, USA.
Antimicrob Agents Chemother. 2011 Nov;55(11):5043-53. doi: 10.1128/AAC.05009-11. Epub 2011 Aug 15.
Small arylamide foldamers designed to mimic the amphiphilic nature of antimicrobial peptides (AMPs) have shown potent bactericidal activity against both Gram-negative and Gram-positive strains without many of the drawbacks of natural AMPs. These foldamers were shown to cause large changes in the permeability of the outer membrane of Escherichia coli. They cause more limited permeabilization of the inner membrane which reaches critical levels corresponding with the time required to bring about bacterial cell death. Transcriptional profiling of E. coli treated with sublethal concentrations of the arylamides showed induction of genes related to membrane and oxidative stresses, with some overlap with the effects observed for polymyxin B. Protein secretion into the periplasm and the outer membrane is also compromised, possibly contributing to the lethality of the arylamide compounds. The induction of membrane stress response regulons such as rcs coupled with morphological changes at the membrane observed by electron microscopy suggests that the activity of the arylamides at the membrane represents a significant contribution to their mechanism of action.
设计用于模拟抗菌肽 (AMPs) 两亲性质的小分子芳酰胺折叠体对革兰氏阴性和革兰氏阳性菌株均具有很强的杀菌活性，而没有天然 AMPs 的许多缺点。这些折叠体被证明会导致大肠杆菌外膜通透性发生巨大变化。它们对内膜的通透性的限制较小，但达到与引起细菌细胞死亡所需时间相对应的临界水平。用亚致死浓度的芳酰胺处理大肠杆菌的转录谱分析显示，与多粘菌素 B 观察到的作用有一些重叠，与膜和氧化应激相关的基因被诱导。周质和外膜中的蛋白质分泌也受到损害，这可能导致芳酰胺化合物的致死性。膜应激反应调节子如 rcs 的诱导以及电子显微镜观察到的膜形态变化表明，芳酰胺在膜上的活性是其作用机制的重要贡献。
