Abstract：
14 novel pleuromutilin derivatives were designed and synthesized as inhibitors against Staphylococcus aureus (S. aureus). The modification was focused on the C22 position of pleuromutilin. We conducted the characterization, in vitro and in vivo biological assessment of the compounds. Compound 18 exhibited the best antibacterial effect against MRSA (MIC = 0.015 μg/mL, MBC = 0.125 μg/mL). Compound 18 was further studied by time-kill kinetic and post-antibiotic effect (PAE) approaches. Besides, most compounds exhibited low cytotoxicity to RAW 264.7 cells. Compound 18 displayed decent bactericidal activity in vivo (-0.51 log10 CFU/mL). Molecular docking study indicated that compound 18 could be located stably at the ribosome (ΔGb = -7.30 kcal/mol). The results revealed that compound 18 might be further developed into a novel antibiotic.
摘要：
设计并合成了14种新型截短侧耳素衍生物作为金黄色葡萄球菌的抑制剂（S.金黄色葡萄球菌）。修饰集中在截短侧耳素的C22位置。我们进行了表征，化合物的体外和体内生物学评估。化合物18对MRSA的抑菌效果最好(MIC=0.015μg/mL,MBC=0.125μg/mL)。通过时间杀灭动力学和抗生素后效应(PAE)方法进一步研究化合物18。此外,大多数化合物对RAW264.7细胞表现出较低的细胞毒性。化合物18在体内显示出良好的杀菌活性(-0.51log10CFU/mL)。分子对接研究表明，化合物18可以稳定地位于核糖体（ΔGb=-7.30kcal/mol）。结果表明，化合物18可能进一步发展成为一种新型抗生素。
