2. Academic Validation
  3. Novel pyridinium cationic pleuromutilin analogues overcoming bacterial multidrug resistance

Novel pyridinium cationic pleuromutilin analogues overcoming bacterial multidrug resistance

  • Eur J Med Chem. 2023 May 5;251:115269. doi: 10.1016/j.ejmech.2023.115269.
Yunpeng Yi 1,  Jiaming Zhang 1,  Jiakun Zuo 2,  Maolu Zhang 1,  Shifa Yang 1,  Zhongli Huang 1,  Guiyu Li 3,  Ruofeng Shang 4,  Shuqian Lin 5
Affiliations

Affiliations

  • 1 Shandong Provincial Animal and Poultry Green Health Products Creation Engineering Laboratory, Institute of Poultry Science, Shandong Academy of Agricultural Science, Jinan, 250100, Shandong, China.
  • 2 Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China.
  • 3 College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, Gansu, China.
  • 4 Key Laboratory of New Animal Drug Project, Gansu Province/Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs/Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, Gansu, China. Electronic address: [email protected].
  • 5 Shandong Provincial Animal and Poultry Green Health Products Creation Engineering Laboratory, Institute of Poultry Science, Shandong Academy of Agricultural Science, Jinan, 250100, Shandong, China. Electronic address: [email protected].
PMID: 36924667 DOI: 10.1016/j.ejmech.2023.115269
Abstract

A series of pyridinium cation-substituted pleuromutilin analogues were designed, synthesized and evaluated for their Antibacterial activities in vitro and in vivo. Most derivatives showed potent Antibacterial activities, especially e4 that displayed the highest Antibacterial activity against multi-drug resistant bacteria and was subjected to time-kill kinetics, resistance studies, cytotoxicity and molecular docking assays. Molecular docking results, scanning electron microscopy and o-nitrophenyl-β-galactopyranoside tests showed that e4 not only inhibited Bacterial protein synthesis but also disrupted Bacterial cell walls. Compound e4 showed an ED50 of 5.68 mg/kg against multi-drug resistant Staphylococcus aureus in infected mice model. In in vivo and in vitro toxicity tests, e4 showed low toxic effects with an LD50 of 879 mg/kg to mice. These results suggest that compound e4 may be considered as a new therapeutic candidate for Bacterial infections.

Keywords

Antibacterial activity; Molecular docking; Multi-drug resistant bacteria; Pleuromutilin derivatives.

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