School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China.
College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan, China.
J Med Chem. 2022 Dec 22;65(24):16879-16892. doi: 10.1021/acs.jmedchem.2c01674. Epub 2022 Dec 13.
Infections caused by methicillin-resistant (MRSA) continue to endanger public health. Here, we report the synthesis of neolignan isomagnolone () and its isomer , and the preparation of a series of novel neolignan-antimicrobial peptide (AMP) mimic conjugates. Notably, conjugates and exhibit potent anti-MRSA activity and , comparable to that of vancomycin, a current effective treatment for MRSA. Moreover, and display not only fast-killing kinetics and low resistance frequency but also low toxicity as well as effects on bacterial biofilms. Mechanism studies reveal that and exhibit rapid bactericidal effects through binding to the phosphatidylglycerol (PG) and cardiolipin (CL) of the bacterial membrane, thereby disrupting the cell membranes and allowing increased reactive oxygen species (ROS) as well as protein and DNA leakage. The results indicate that these neolignan-AMP mimic conjugates could be promising antimicrobial candidates for combating MRSA infections.
耐甲氧西林金黄色葡萄球菌（MRSA）引起的感染继续威胁着公众健康。在这里，我们报告了新木脂素异马钱素（）及其异构体的合成，以及一系列新型新木脂素-抗菌肽（AMP）模拟物缀合物的制备。值得注意的是，缀合物和对耐甲氧西林金黄色葡萄球菌具有很强的抗活性，与万古霉素相当，万古霉素是目前治疗耐甲氧西林金黄色葡萄球菌的有效药物。此外，和不仅具有快速杀菌动力学和低耐药频率，而且毒性低，对细菌生物膜也有作用。机制研究表明，和通过与细菌膜的磷脂酰甘油（PG）和心磷脂（CL）结合，表现出快速杀菌作用，从而破坏细胞膜，并允许增加活性氧（ROS）以及蛋白质和 DNA 泄漏。结果表明，这些新木脂素-AMP 模拟缀合物可能是对抗耐甲氧西林金黄色葡萄球菌感染的有前途的抗菌候选物。
