Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.
Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China.
Molecules. 2021 Jun 8;26(12):3502. doi: 10.3390/molecules26123502.
A novel pleuromutilin derivative, 22-(4-(2-(4-nitrophenyl-piperazin-1-yl)-acetyl)-piperazin-1-yl)-22-deoxypleuromutilin (NPDM), was synthesized in our laboratory and proved excellent antibacterial activity against methicillin-resistant (MRSA). In this study, more methods were used to further study its preliminary pharmacological effect. The antibacterial efficacy and toxicity of NPDM were evaluated using tiamulin as the reference drug. The in vitro antibacterial activity study showed that NPDM is a potent bactericidal agent against MRSA that induced time-dependent growth inhibition and a concentration-dependent post-antibiotic effect (PAE). Toxicity determination showed that the cytotoxicity of NPDM was slightly higher than that of tiamulin, but the acute oral toxicity study proved that NPDM was a low-toxic compound. In an in vivo antibacterial effect study, NPDM exhibited a better therapeutic effect than tiamulin against MRSA in a mouse thigh infection model as well as a mouse systemic infection model with neutropenia. The 50% effective dose (ED) of NPDM in a infection model was 50.53 mg/kg. The pharmacokinetic properties of NPDM were also measured, which showed that NPDM was a rapid elimination drug in mice.
一种新型截短侧耳素衍生物 22-(4-(2-(4-硝基苯基-哌嗪-1-基)-乙酰基)-哌嗪-1-基)-22-去氧截短侧耳素（NPDM）由我们实验室合成，被证明对耐甲氧西林金黄色葡萄球菌（MRSA）具有优异的抗菌活性。在本研究中，采用了更多的方法来进一步研究其初步的药理学作用。采用泰妙菌素作为参考药物，评估了 NPDM 的抗菌功效和毒性。体外抗菌活性研究表明，NPDM 是一种针对 MRSA 的强效杀菌剂，可诱导时间依赖性生长抑制和浓度依赖性抗生素后效应（PAE）。毒性测定表明，NPDM 的细胞毒性略高于泰妙菌素，但急性口服毒性研究证明 NPDM 是一种低毒化合物。在体内抗菌效果研究中，NPDM 在 MRSA 感染的小鼠大腿感染模型和中性粒细胞减少症的小鼠全身感染模型中显示出比泰妙菌素更好的治疗效果。在感染模型中，NPDM 的 50%有效剂量（ED）为 50.53mg/kg。还测量了 NPDM 的药代动力学特性，结果表明 NPDM 是一种在小鼠体内快速消除的药物。
