Department of Chemistry and Biochemistry, Columbia, SC, 29208, United States.
Department of Pathology, Microbiology and Immunology, University of South Carolina, School of Medicine, Columbia, SC, 29209, United States.
Nat Commun. 2018 Dec 7;9(1):5231. doi: 10.1038/s41467-018-07651-7.
Bacterial infections and antibiotic resistance, particularly by Gram-negative pathogens, have become a global healthcare crisis. We report the design of a class of cationic antimicrobial polymers that cluster local facial amphiphilicity from repeating units to enhance interactions with bacterial membranes without requiring a globally conformational arrangement associated with highly unfavorable entropic loss. This concept of macromolecular architectures is demonstrated with a series of multicyclic natural product-based cationic polymers. We have shown that cholic acid derivatives with three charged head groups are more potent and selective than lithocholic and deoxycholic counterparts, particularly against Gram-negative bacteria. This is ascribed to the formation of true facial amphiphilicity with hydrophilic ion groups oriented on one face and hydrophobic multicyclic hydrocarbon structures on the opposite face. Such local facial amphiphilicity is clustered via a flexible macromolecular backbone in a concerted way when in contact with bacterial membranes.
细菌感染和抗生素耐药性，特别是革兰氏阴性病原体的耐药性，已成为全球医疗保健的危机。我们报告了一类阳离子抗菌聚合物的设计，这些聚合物通过重复单元聚集局部面两亲性，增强与细菌膜的相互作用，而不需要与高度不利的熵损失相关的全局构象排列。这种大分子结构的概念通过一系列基于多环天然产物的阳离子聚合物得到了证明。我们已经表明，具有三个带电头基团的胆酸衍生物比石胆酸和去氧胆酸的对应物更有效和更具选择性，特别是对革兰氏阴性菌。这归因于真正的面两亲性的形成，亲水离子基团朝向一个面，疏水性多环烃结构朝向相反的面。当与细菌膜接触时，这种局部面两亲性通过柔性大分子主链以协同的方式聚集。
