Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093, Warsaw, Poland.
Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Zwirki i Wigury 101, 02-089, Warsaw, Poland.
Eur J Med Chem. 2023 Nov 5;259:115700. doi: 10.1016/j.ejmech.2023.115700. Epub 2023 Aug 2.
The overuse of antibiotics has led to a rise in infections caused by multidrug-resistant bacteria, resulting in a need for new antibacterial compounds with different modes of action. In this paper, we describe a new class of compounds called lipooligoureas, which are foldamer-based mimetics of antimicrobial lipopeptides. The lipooligoureas consist of an acyl chain connected to the N-terminus of an oligourea head group that exhibits a well-defined 2.5-helix secondary structure, which is further stabilized by the attachment of the lipophilic chain to the oligourea moiety. These compounds meet the established criteria for membranolytic compounds by possessing an amphiphilic structure that promotes the internalization and partitioning of the molecules into the lipid membrane. The presence of positively charged urea residues promotes electrostatic interactions with the negatively charged bacterial membrane. The subtle structural differences in oligourea head group influence the compounds' aggregation behavior, with the number and position of positively charged urea residues correlating with their aggregation ability. The biological activity of these compounds in inhibiting bacterial growth is correlated with their ability to aggregate, with stronger antibacterial properties exhibited by those that aggregate more easily. However, the concentration inhibiting bacterial growth is significantly lower than the critical aggregation concentration values, suggesting that the mechanism of action involves the monomeric forms of lipooligoureas. Nonetheless, a mechanism based on membrane-induced aggregation cannot be ruled out. The lipooligoureas exhibit higher activity towards Gram-positive bacteria than against Gram-negative bacteria, which is indicative of certain selectivity of these compounds. It is also demonstrated that lipooligoureas exhibit increased stability against proteolytic degradation in human blood serum.
抗生素的过度使用导致了多药耐药菌引起的感染增加，因此需要具有不同作用模式的新型抗菌化合物。在本文中，我们描述了一类称为脂寡聚脲的新型化合物，它们是抗菌脂肽的基于折叠体的模拟物。脂寡聚脲由酰基链连接到寡脲头基团的 N 末端组成，该头基团表现出明确的 2.5 螺旋二级结构，通过将疏脂链连接到寡脲部分进一步稳定。这些化合物通过具有促进分子内化和分配到脂质膜中的两亲性结构来满足溶膜化合物的既定标准。带正电荷的脲残基的存在促进了与带负电荷的细菌膜的静电相互作用。寡脲头基团的细微结构差异会影响化合物的聚集行为，带正电荷的脲残基的数量和位置与它们的聚集能力相关。这些化合物抑制细菌生长的生物学活性与其聚集能力相关，更容易聚集的化合物具有更强的抗菌性能。然而，抑制细菌生长的浓度明显低于临界聚集浓度值，这表明作用机制涉及脂寡聚脲的单体形式。尽管如此，不能排除基于膜诱导聚集的机制。脂寡聚脲对革兰氏阳性菌的活性高于对革兰氏阴性菌的活性，这表明这些化合物具有一定的选择性。还证明了脂寡聚脲在人血清中对蛋白水解降解的稳定性增加。
