Shen Bo-Yuan, Wang Ming-Ming, Xu Shuai-Min, Gao Chen, Wang Meng, Li Sen, Ampomah-Wireko Maxwell, Chen Sheng-Cong, Yan Da-Chao, Qin Shangshang, Zhang En
School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Zhengzhou, 450001, PR China.
The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, PR China.
Eur J Med Chem. 2022 Dec 15;244:114885. doi: 10.1016/j.ejmech.2022.114885. Epub 2022 Oct 28.
Bacterial resistance is a growing threat to public health and a significant barrier to anti-infective treatment. Consequently, the development of novel antibacterial strategies to address this issue is critical. Herein, we developed a series of chalcone-alkyl-lysine compounds by mimicking the chemical structure and antibacterial properties of cationic antimicrobial peptides. Most of the compounds showed significant antibacterial activity against Gram-positive and Gram-negative bacteria. Compound 6d displayed potent antibacterial activity against Gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis) and Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), with MICs of 1-4 μg/mL. In addition, 6d exhibited excellent antibacterial activity against clinical MRSA and NDM-positive isolates, bactericidal properties, low resistance frequency. The mechanism studies revealed that compound 6d destroys bacterial cell membranes by interacting with phosphatidylglycerol (PG), causing the production of reactive oxygen species (ROS) and the leakage of nucleic acids, resulting in bacterial death. Furthermore, compound 6d did not exhibit any observable toxicity in HeLa and HEK293 cells at 8 × MIC. As a result, the findings suggest that compound 6d has potential therapeutic effects against bacterial infections and could be a promising drug candidate for future research.
细菌耐药性对公众健康构成日益严重的威胁，也是抗感染治疗的重大障碍。因此，开发新的抗菌策略来解决这一问题至关重要。在此，我们通过模仿阳离子抗菌肽的化学结构和抗菌特性，开发了一系列查尔酮-烷基-赖氨酸化合物。大多数化合物对革兰氏阳性菌和革兰氏阴性菌均表现出显著的抗菌活性。化合物6d对革兰氏阳性菌（金黄色葡萄球菌和粪肠球菌）和革兰氏阴性菌（大肠杆菌和铜绿假单胞菌）显示出强效抗菌活性，最低抑菌浓度（MIC）为1 - 4μg/mL。此外，6d对临床耐甲氧西林金黄色葡萄球菌（MRSA）和新德里金属β-内酰胺酶阳性（NDM阳性）分离株表现出优异的抗菌活性、杀菌特性以及低耐药频率。机制研究表明，化合物6d通过与磷脂酰甘油（PG）相互作用破坏细菌细胞膜，导致活性氧（ROS）的产生和核酸泄漏，从而致使细菌死亡。此外，化合物6d在8倍MIC浓度下对HeLa和HEK293细胞未表现出任何可观察到的毒性。因此，研究结果表明化合物6d对细菌感染具有潜在治疗作用，可能是未来研究中一种有前景的候选药物。
