Anti-methicillin-resistant Staphylococcus aureus activity and safety evaluation of 14-O-[( 5-ethoxycarbonyl-4,6-dimethylp yrimidine-2-yl) thioacetyl] mutilin (EDT)

文献类型： 外文期刊

第一作者： Zhou, Yuhang

作者： Zhou, Yuhang;Zhang, Hongjuan;Liu, Qinqin;Wang, Shengyi;Pu, Wanxia;Shang, Ruofeng;Yi, Yunpeng;Yang, Jing

作者机构： Lanzhou Inst Husb & Pharmaceut Sci CAAS, Minist Agr & Rural Affairs, Gansu Prov Key Lab Vet Pharmaceut Dev, Key Lab New Anim Drug Project,, Lanzhou 730050, Peoples R China;Shandong Acad Agr Sci, Inst Poultry Sci, Shandong Prov Anim & Poultry Green Hlth Prod Creat, Jinan 250023, Peoples R China;Gansu Anal & Res Ctr, Lanzhou 730000, Peoples R China

期刊名称：SCIENTIFIC REPORTS （ 2022影响因子：4.6； 五年影响因子：4.9 ）

ISSN： 2045-2322

年卷期： 2023 年 13 卷 1 期

页码：

收录情况： SCI

摘要： Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) have threated the public health worldwide, which emphasizes the urgent need for new drugs with novel mechanism of actions. 14-O-[(5-ethoxycarbonyl-4,6-dimethylpyrimidine-2-yl) thioacetyl] mutilin (EDT) is a pleuromutilin compound with high activity against several Gram-positive bacteria in vitro and in vivo. This study aimed to verifying the potential anti-MRSA activity and evaluating the safety of EDT. In in vitro antibacterial activity assays, EDT exhibited potent antibacterial activity against MRSA isolated from clinic (minimum inhibitory concentration = 0.0313-0.125 mu g/ mL), increased post-antibiotic effect (PAE) values and limited potential for the development of resistance. Docking model and green fluorescent protein (GFP) inhibition assay further elucidated the higher antibacterial activities of EDT via mechanism of action. In safety evaluation, EDT exhibited low cytotoxic effect and acute oral toxicity in mice and avoided to significantly increase the number of revertant colonies of six tested strains in the Ames study. Furthermore, EDT displayed a moderate inhibitory effect on CYP3A4 and moderate stability in mouse and human liver microsomes, providing a promising agent for the development of new antimicrobial candidate.

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