Zhang Chao, Yi Yunpeng, Chen Jiongran, Xin Rensheng, Yang Zhen, Guo Zhiting, Liang Jianping, Shang Ruofeng
Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China.
Molecules. 2015 Mar 24;20(4):5299-312. doi: 10.3390/molecules20045299.
A new pleuromutilin derivative with excellent antibacterial activity, 14-O-[(2-amino-1,3,4-thiadiazol-5-yl) thioacetyl] mutilin (ATTM), may serve as a possible lead compound for the development of antibacterial drugs. However, in vivo efficacy and toxicity evaluations of this compound have not been performed. In this study, we evaluated the efficacy of ATTM by measuring the survival of mice after a lethal challenge with methicillin-resistant Staphylococcus aureus (MRSA), and the 50% effective dose (ED50) was 5.74 mg/kg by the intravenous route. In an oral single-dose toxicity study, ATTM was orally administered to mice at different doses and the 50% lethal dose (LD50) was calculated to be 2304.4 mg/kg by the Bliss method. The results of the subchronic oral toxicity study in rats showed no mortality, exterior signs of toxicity, or differences in the total weight gain or relative organ weights between the treated groups and control group after administration. The hematological and serum biochemical data showed no differences between the treated and control groups, except for the levels of alkaline phosphatase (ALP), creatinine (CR) and blood glucose (GLU), which were significantly different in the high-dose group. The differences in the histopathological findings between the treated groups and the control group were not considered to be treatment-related. Our results indicated that the no observed adverse effect level (NOAEL) for ATTM was 5 mg/kg in this study.
一种具有优异抗菌活性的新型截短侧耳素衍生物，14-O-[(2-氨基-1,3,4-噻二唑-5-基)硫代乙酰基]截短侧耳素（ATTM），可能作为开发抗菌药物的潜在先导化合物。然而，尚未对该化合物进行体内疗效和毒性评估。在本研究中，我们通过测量耐甲氧西林金黄色葡萄球菌（MRSA）致死攻击后小鼠的存活率来评估ATTM的疗效，静脉给药的50%有效剂量（ED50）为5.74 mg/kg。在口服单剂量毒性研究中，以不同剂量给小鼠口服ATTM，通过 Bliss 法计算得出50%致死剂量（LD50）为2304.4 mg/kg。大鼠亚慢性口服毒性研究结果显示，给药后治疗组与对照组之间无死亡、无明显毒性体征，总体重增加或相对器官重量也无差异。血液学和血清生化数据显示，治疗组与对照组之间无差异，但高剂量组的碱性磷酸酶（ALP）、肌酐（CR）和血糖（GLU）水平有显著差异。治疗组与对照组之间组织病理学结果的差异不被认为与治疗有关。我们的结果表明，在本研究中ATTM的无观察到不良反应水平（NOAEL）为5 mg/kg。
