College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang 310018, PR. China.
College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Key Laboratory of Organosilicon Material Technology, Hangzhou Normal University, Hangzhou 311121, P. R. China.
ACS Appl Bio Mater. 2024 Nov 18;7(11):7730-7739. doi: 10.1021/acsabm.4c01305. Epub 2024 Nov 2.
The increasing number of infections caused by pathogenic bacteria has severely affected human society. More and more deaths were originated from Gram-positive methicillin-resistant (MRSA) infection each year. The potential and excellent bacteriostatic activity and resistance to biofilm formation of pillar[5]arene with different functional groups attract important attention to further study the relationship between antimicrobial activity and cytotoxicity by varying the length of the hydrophobic chain, the number of positive charges, and the hydrophobic/hydrophilic balance of the molecule. In this work, four pyridinium-based cationic pillar[5]arene (s) with linear aliphatic chains of different lengths were synthesized. After systematic characterization, their inhibition activities against were investigated. It revealed that (six methylenes in each linker) exhibited excellent inhibition activity against (ATCC 6538) with a minimum inhibitory concentration (MIC) of 3.91 μg/mL and a minimum bactericidal concentration (MBC) of 62.50 μg/mL. As expected, exhibited the strongest antibiofilm ability and negligible antimicrobial resistance even after the 20th passage. A study of the action mechanism of selected s on the bacterial membrane depolarization and permeability by transmission electron microscopy (TEM) disclosed that the cationic pyridine groups of s inserted into the negatively charged bacterial membranes, thereby leading to membranolysis, cytoplasmic content leakage, and cell death. Importantly, s all showed very low toxicity to mammalian cells (L929 and HBZY-1), which provided a significant reference for the construction of hypotoxic antibacterial biomaterials for multiple drug-resistant bacteria based on pyridinium-grafted cationic macrocycles with controllable hydrophobic chain lengths.
致病细菌感染的数量不断增加，严重影响了人类社会。每年越来越多的人死于革兰氏阳性耐甲氧西林金黄色葡萄球菌 (MRSA) 感染。具有不同官能团的柱芳烃具有潜在的和优异的抑菌活性以及抗生物膜形成能力，这引起了人们对通过改变疏水性链的长度、正电荷的数量以及分子的疏水性/亲水性平衡来进一步研究抗菌活性和细胞毒性之间的关系的重要关注。在这项工作中，合成了四个具有不同长度线性脂肪链的基于吡啶鎓的阳离子柱[5]芳烃（s）。经过系统的表征，研究了它们对 的抑制活性。结果表明， （每个连接体中有六个亚甲基）对 （ATCC 6538）表现出优异的抑制活性，最小抑菌浓度（MIC）为 3.91 μg/mL，最小杀菌浓度（MBC）为 62.50 μg/mL。正如预期的那样， 即使经过 20 次传代，也表现出最强的抗生物膜能力和可忽略不计的抗菌耐药性。通过透射电子显微镜（TEM）研究选定的 s 对细菌膜去极化和通透性的作用机制表明，s 的阳离子吡啶基团插入带负电荷的细菌膜中，从而导致膜溶解、细胞质内容物泄漏和细胞死亡。重要的是，s 对哺乳动物细胞（L929 和 HBZY-1）的毒性非常低，这为基于具有可控疏水性链长的吡啶接枝阳离子大环构建针对多药耐药菌的低毒性抗菌生物材料提供了重要参考。
