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 Staphylococcus aureus (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 (ED₅₀) of NPDM in a Galleria mellonella 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.

中文翻译：

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一种有前景的抗菌剂的抗菌活性：22-(4-(2-(4-Nitrophenyl-piperazin-1-yl)-acetyl)-piperazin-1-yl)-22-deoxypleuromutilin

我们实验室合成了一种新型截短侧耳素衍生物 22-(4-(2-(4-nitrophenyl-piperazin-1-yl)-acetyl)-piperazin-1-yl)-22-deoxypleuromutilin (NPDM)对耐甲氧西林金黄色葡萄球菌的抗菌活性(MRSA)。本研究采用更多的方法对其初步药理作用进行进一步研究。以泰妙菌素为参比药物评价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。在体内抗菌作用研究中，NPDM 在小鼠大腿感染模型以及中性粒细胞减少症小鼠全身感染模型中显示出比泰妙菌素更好的抗 MRSA 治疗效果。50% 有效剂量 (ED ₅₀) 在大蜡螟感染模型中的 NPDM为 50.53 毫克/公斤。还测定了NPDM的药代动力学特性，表明NPDM是小鼠体内的快速消除药物。