Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China.
Drug Dev Res. 2023 Nov;84(7):1437-1452. doi: 10.1002/ddr.22095. Epub 2023 Aug 3.
A series of pleuromutilin derivatives containing benzimidazole were designed, synthesized, and evaluated for their antibacterial activities against Methicillin-resistant Staphylococcus aureus (MRSA) in this study. The in vitro antibacterial activities of the synthesized derivatives against four strains of S. aureus (MRSA ATCC 43300, S. aureus ATCC 29213, S. aureus 144, and S. aureus AD3) were determined by the broth dilution method. Among these derivatives, compound 58 exhibited superior in vitro antibacterial effect against MRSA (minimal inhibitory concentration [MIC] = 0.0625 μg/mL) than tiamulin (MIC = 0.5 μg/mL). Compound 58 possessed a faster bactericidal kinetic and a longer post-antibiotic effect time against MRSA than tiamulin. Meanwhile, at 8 μg/mL concentration, compound 58 did not display obviously cytotoxic effect on the RAW 264.7 cells. In addition, compound 58 (-2.04 log CFU/mL) displayed superior in vivo antibacterial efficacy than tiamulin (-1.02 log CFU/mL) in reducing MRSA load in mice thigh infection model. In molecular docking study, compound 58 can successfully attach to the 50S ribosomal active site (the binding free energy is -8.11 kcal/mol). Therefore, compound 58 was a potential antibacterial candidate for combating MRSA infections.
本研究设计、合成了一系列含苯并咪唑的截短侧耳素衍生物，并评估了它们对耐甲氧西林金黄色葡萄球菌（MRSA）的体外抗菌活性。采用肉汤稀释法测定了合成衍生物对 4 株金黄色葡萄球菌（MRSA ATCC 43300、金黄色葡萄球菌 ATCC 29213、金黄色葡萄球菌 144 和金黄色葡萄球菌 AD3）的体外抗菌活性。在这些衍生物中，化合物 58 对 MRSA 的体外抗菌效果优于泰妙菌素（MIC = 0.0625 μg/mL）（MIC = 0.5 μg/mL）。化合物 58 对 MRSA 的杀菌动力学更快，抗生素后效应时间更长。同时，在 8 μg/mL 浓度下，化合物 58 对 RAW 264.7 细胞没有明显的细胞毒性作用。此外，化合物 58（-2.04 log CFU/mL）在减少小鼠大腿感染模型中 MRSA 负荷方面的体内抗菌疗效优于泰妙菌素（-1.02 log CFU/mL）。在分子对接研究中，化合物 58 可以成功地附着在 50S 核糖体的活性部位（结合自由能为-8.11 kcal/mol）。因此，化合物 58 是一种有潜力的抗 MRSA 感染的抗菌候选药物。
