Key Laboratory of New Animal Drug Project of Gansu Province; Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, P. R. China; Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, 730050 Lanzhou, China.
Key Laboratory of New Animal Drug Project of Gansu Province; Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, P. R. China; Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, 730050 Lanzhou, China.
Pharmacol Res. 2018 Mar;129:424-431. doi: 10.1016/j.phrs.2017.11.010. Epub 2017 Nov 10.
A new pleuromutilin derivative, 14-O-[(4-Amino-6-hydroxy-pyrimidine-2-yl)thioacetyl] mutilin (APTM), has been synthesized and proved most potent antibacterial agent in in vitro assays, suggesting that further development of this compound may lead to a promising antibacterial drug. In this study, we further evaluated the cytotoxicity, antibacterial efficacy and the pharmacokinetic profile of APTM. In BRL 3A cells, 50% of viability was obtained when 363μg/mL of APTM was used, while retapamulin and tiamulin fumarate needed 49 and 28μg/mL, respectively, to reach this viability. Compared to tiamulin fumarate, APTM showed higher inhibition efficacy and faster bactericidal activity against S. aureus and lower 50% effective dose (ED) in mice after a lethal challenge with methicillin-resistant Staphylococcus aureus (MRSA). Docking experiment for APTM showed a similar binding pattern with tiamulin. Furthermore, a simple, accurate and sensitive HPLC method for the determination of APTM in rabbit plasma was developed and successfully applied to pharmacokinetic study, in which the half life (t), clearance rate (Cl) and the area under the plasma concentration-time curve (AUC) were 3.37h, 0.35L/h/kg and 70.68μg·h/m, respectively.
一种新的截短侧耳素衍生物，14-O-[(4-氨基-6-羟基嘧啶-2-基)硫代乙酰基]截短侧耳素（APTM）已被合成，并在体外试验中被证明是最有效的抗菌剂，这表明该化合物的进一步开发可能会导致一种有前途的抗菌药物。在本研究中，我们进一步评估了 APTM 的细胞毒性、抗菌功效和药代动力学特征。在 BRL 3A 细胞中，当使用 363μg/mL 的 APTM 时，细胞活力达到 50%，而瑞他帕林和富马酸替米考星分别需要 49μg/mL 和 28μg/mL 才能达到这一活力水平。与富马酸替米考星相比，APTM 对金黄色葡萄球菌的抑制效果更高，杀菌活性更快，对耐甲氧西林金黄色葡萄球菌（MRSA）的半数有效剂量（ED）更低。APTM 的对接实验显示出与替米考星相似的结合模式。此外，还建立了一种简单、准确、灵敏的 HPLC 法测定兔血浆中的 APTM，并成功应用于药代动力学研究，其中半衰期（t）、清除率（Cl）和血浆浓度-时间曲线下面积（AUC）分别为 3.37h、0.35L/h/kg 和 70.68μg·h/m。
