Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, P. R. China.
Guangdong Key Laboratory of Optical Fiber Sensing and Communications, Institute of Photonics Technology, Jinan University, Guangzhou 510632, Guangdong, P. R. China.
J Med Chem. 2020 Sep 10;63(17):9284-9299. doi: 10.1021/acs.jmedchem.0c00433. Epub 2020 Sep 1.
The development of new antimicrobial agents capable of curing drug-resistant bacteria-induced infections is becoming a major challenge to the global healthcare system. To develop antimicrobials with new molecular entities, a series of novel carbazole-based compounds were designed and synthesized by biomimicking the structural properties and biological function of antimicrobial peptides. Compound was selected as a lead compound from the structure-activity relationship analyses and biological activity evaluation. Compound showed excellent antimicrobial activity against Gram-positive bacteria (MICs = 0.78-1.56 μg/mL), poor hemolytic activity (HC > 200 μg/mL), and low cytotoxicity to mammalian cells. Compound had fast bactericidal properties and effectively prevented bacterial resistance in laboratory simulations. Antibacterial mechanism studies revealed that compound directly destroyed bacterial cell membranes, leading to bacterial deaths. Importantly, compound displayed an excellent efficacy in a murine bacterial keratitis model caused by ATCC29213.
开发能够治愈耐药菌引起的感染的新型抗菌药物正成为全球医疗保健系统的主要挑战。为了开发具有新分子实体的抗菌药物，通过模拟抗菌肽的结构特性和生物学功能，设计并合成了一系列新型咔唑类化合物。通过结构-活性关系分析和生物活性评价，选择化合物 作为先导化合物。化合物 对革兰氏阳性菌（MICs=0.78-1.56μg/mL）具有优异的抗菌活性，溶血活性差（HC>200μg/mL），对哺乳动物细胞的细胞毒性低。化合物 具有快速杀菌特性，并能有效防止实验室模拟中的细菌耐药性。抗菌机制研究表明，化合物 直接破坏细菌细胞膜，导致细菌死亡。重要的是，化合物 在由 ATCC29213 引起的小鼠细菌性角膜炎模型中显示出优异的疗效。
