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

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

  • Pharmacol Res. 2018 Mar:129:424-431. doi: 10.1016/j.phrs.2017.11.010.
Ruofeng Shang 1,  Yunpeng Yi 2,  Chao Zhang 3,  Yunxing Fu 2,  Jianping Liang 2,  Wanxia Pu 4
Affiliations

Affiliations

  • 1 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. Electronic address: shangrf1974@163.com.
  • 2 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.
  • 3 Lianyungang Animal Health Inspection Institute, Lianyungang, 222000, Lianyungang, China.
  • 4 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. Electronic address: wanxiapu@163.com.
PMID: 29133214 DOI: 10.1016/j.phrs.2017.11.010
Abstract

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 (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 (t1/2), clearance rate (Cl) and the area under the plasma concentration-time curve (AUC0→∞) were 3.37h, 0.35L/h/kg and 70.68μg·h/m, respectively.

Keywords

APTM; Antibacterial activity; Inhibition efficacy; Molecular docking; Pharmacokinetic.

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