Antibacterial activity and pharmacokinetic profile of a promising antibacterial agent: 14-O-[(4-Amino-6-hydroxy-pyrimidine-2-yl)thioacetyl] mutilin

作者：Shang, Ruofeng; Yi, Yunpeng; Zhang, Chao; Fu, Yunxing; Liang, Jianping; Pu, Wanxia^*

来源：Pharmacological Research, 2018, 129: 424-431.

DOI：10.1016/j.phrs.2017.11.010

• APTM
• Antibacterial activity
• Inhibition efficacy
• Molecular docking
• Pharmacokinetic

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 363 mu g/mL of APTM was used, while retapamulin and tiamulin fumarate needed 49 and 28 mu g/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 (ED50) 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(1/2)), clearance rate (CI) and the area under the plasma concentration-time curve (AUC(0 ->infinity)) were 3.37 h, 0.35 L/h/kg and 70.68 mu g.h/m respectively.

• 出版日期2018-3
• 单位中国农业科学院