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  3. Design, synthesis, and biological evaluation of novel pleuromutilin derivatives with methicillin-resistant Staphylococcus aureus -targeting phenol linker groups

Design, synthesis, and biological evaluation of novel pleuromutilin derivatives with methicillin-resistant Staphylococcus aureus -targeting phenol linker groups

  • Eur J Med Chem. 2025 Jan 15:282:117061. doi: 10.1016/j.ejmech.2024.117061.
Yunpeng Yi 1,  Jiaming Zhang 2,  Shuqian Lin 1,  Haiting Wang 1,  Guiyu Li 1,  Shifa Yang 1,  Ruofeng Shang 3,  Rongling Zhang 4,  Fei Li 5
Affiliations

Affiliations

  • 1 Shandong Provincial Engineering Research Center for Animal Health Products, Institute of Poultry Science, Shandong Academy of Agricultural Science, Jinan, 250100, Shandong, China.
  • 2 Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Sciences, Lanzhou, 730050, Gansu, China.
  • 3 Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, China; Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Sciences, Lanzhou, 730050, Gansu, China.
  • 4 Shandong Provincial Engineering Research Center for Animal Health Products, Institute of Poultry Science, Shandong Academy of Agricultural Science, Jinan, 250100, Shandong, China. Electronic address: zhangrongling@saas.ac.cn.
  • 5 Henan Key Laboratory of Rare Earth Functional Materials, Henan International Joint Laboratory of Biomedical Nanomaterials, Zhoukou Normal University, Zhoukou, 466001, Henan, China. Electronic address: lifei@zknu.edu.cn.
PMID: 39550822 DOI: 10.1016/j.ejmech.2024.117061
Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) remains a significant global health threat, necessitating the development of new therapeutic agents. Pleuromutilin derivatives offer a promising solution due to their potent Antibacterial activity, particularly against Gram-positive bacteria such as MRSA. In this study, we synthesized a series of pleuromutilin derivatives with phenol linker containing C14 side chains and evaluated in vitro and in vivo Antibacterial activities. Several compounds showed potent activity against MRSA and Staphylococcus aureus with minimal inhibitory concentrations (MICs) as low as 0.03125 μg/mL. In particular, compounds a4 and b4 showed rapid bactericidal activity, significantly reducing MRSA loads in time-kill kinetics and exhibiting slower resistance development compared to tiamulin. In vivo, compound a4 showed superior efficacy in reducing MRSA-induced lung damage in a mouse model at a lower effective dose (ED50 = 6.48 mg/kg) compared to tiamulin (ED50 = 11.38 mg/kg). Molecular docking and molecular dynamics studies also showed that compound a4 binds strongly to the ribosomal peptidyl transferase center (PTC), a key target for pleuromutilin derivatives. These results suggest that compound a4, with its enhanced Antibacterial activity and low resistance potential, is a promising candidate for further development as an effective treatment for MRSA infections.

Keywords

Antibacterial activity; MRSA; Molecular docking; Pleuromutilin derivatives.

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