2. Academic Validation
  3. Design, synthesis, and evaluation of novel pleuromutilin aryl acrylate derivatives as promising broad-spectrum antibiotics especially for combatting multi-drug resistant gram-negative bacteria

Design, synthesis, and evaluation of novel pleuromutilin aryl acrylate derivatives as promising broad-spectrum antibiotics especially for combatting multi-drug resistant gram-negative bacteria

  • Eur J Med Chem. 2023 Nov 5;259:115653. doi: 10.1016/j.ejmech.2023.115653.
Min Li 1,  Jialin Li 2,  Jingyi Li 2,  Jie Zhang 2,  Yuqing Zhao 2,  Wenying Li 3,  Yunfei Zhang 2,  Jinrong Hu 2,  Xiaolin Xie 4,  Dezhu Zhang 4,  Han Li 2,  Qianqian Zhao 5,  Hong Gao 6,  Chengyuan Liang 7
Affiliations

Affiliations

  • 1 College of Pharmacy, Xinjiang Medical University, No.567 Shangde North Road, Urumqi, Xinjiang, 830001, PR China. Electronic address: limin831120@163.com.
  • 2 School of Biological and Pharmaceutical Sciences, Shaanxi University of Science & Technology, Xi'an, 710021, PR China.
  • 3 College of Pharmacy, Xinjiang Medical University, No.567 Shangde North Road, Urumqi, Xinjiang, 830001, PR China.
  • 4 Shaanxi Panlong Pharmaceutical Group Co., Ltd., Xi'an, 710025, PR China.
  • 5 School of Biological and Pharmaceutical Sciences, Shaanxi University of Science & Technology, Xi'an, 710021, PR China. Electronic address: zhaoqianqian@sust.edu.cn.
  • 6 Shaanxi Pioneer Biotech Co., Ltd., Xi'an, 710021, PR China.
  • 7 School of Biological and Pharmaceutical Sciences, Shaanxi University of Science & Technology, Xi'an, 710021, PR China. Electronic address: chengyuanliang@gmail.com.
PMID: 37531743 DOI: 10.1016/j.ejmech.2023.115653
Abstract

The emergence of drug-resistant strains presents a grave challenge for traditional Antibiotics, underscoring the exigency of exploring novel Antibacterial drugs. To address this, the present study endeavors to design and synthesize a collection of pleuromutilin aromatic acrylate derivatives, guided by combination principles. The Antibacterial activity and structure-activity relationship of these derivatives were evaluated, and most of the derivatives displayed moderate to excellent Antibacterial activity against both Gram-positive bacteria and Gram-negative bacteria. Among these derivatives, 5g exhibited the strongest Antibacterial activity, with MIC (minimum inhibitory concentration) values ranging from 1-32 μg/mL, and a MIC value against clinically isolated drug-resistant strains of 4-64 μg/mL. Additionally, 5g exhibited negligible cytotoxicity, superior anti-mycoplasma activity, and a greater propensity to perturb Bacterial cell membranes. Notably, the administration of 5g resulted in an increased survival rate of MRSA (Methicillin-resistant Staphylococcus aureus)-infected mice, with an ED50 (median effective dose) value of 9.04 mg/kg. These results indicated the potential of 5g to be further developed as an Antibacterial drug for the clinical treatment of drug-resistant Bacterial infections.

Keywords

Antibiotics; Broad-spectrum; Gram-negative bacteria; Multi-drug resistant bacteria; Pleuromutilin.

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