化学
噻唑
广谱
抗菌活性
组合化学
体内
抗菌剂
金黄色葡萄球菌
微生物学
抗菌剂
立体化学
抗生素
有机化学
生物化学
细菌
生物
遗传学
生物技术
作者
Juan Xia,Liang Xin,Jingyi Li,Lei Tian,Kang-Xiong Wu,Shaojun Zhang,Wenjing Yan,Han Li,Qianqian Zhao,Chengyuan Liang
标识
DOI:10.1021/acs.jmedchem.2c02135
摘要
The quaternization of compounds has emerged as a promising molecular design strategy for the development of antibiotics. Herein, we report the design, synthesis, antibacterial activities, and structure-activity relationships of a series of novel pleuromutilin derivatives containing a quaternary amine C-14 side chain. Most of these derivatives exhibited broad-spectrum antibacterial activity against the tested bacteria. 10b was the most effective antibacterial agent that displayed excellent antibacterial activity against five clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates, remarkable antimycoplasma activity, rapid bactericidal effects, and a strong ability to damage bacterial biofilms. Further mechanistic studies indicated that 10b destroyed bacterial cell membranes to exert its antibacterial effects. Moreover, 10b exhibited high survival protection and potent in vivo antibacterial efficacy (ED50 = 4.94 mg/kg) in a mouse model of systemic MRSA infection. These findings suggest that 10b is a promising candidate for the treatment of multi-drug-resistant infectious diseases, especially MRSA infections.
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