2. Academic Validation
  3. Discovery of novel triphenylphosphonium conjugated pleuromutilin with enhanced anti-MRSA effect and broaden antibacterial spectrum

Discovery of novel triphenylphosphonium conjugated pleuromutilin with enhanced anti-MRSA effect and broaden antibacterial spectrum

  • Eur J Med Chem. 2025 Sep 15:294:117731. doi: 10.1016/j.ejmech.2025.117731.
Bo Feng 1,  Huabin Hu 2,  Jin Xiang 3,  Guangxu Wu 3,  Zihao Zhu 3,  Gao Zhang 3,  Jie Zhang 3,  Weidong Pan 4,  Wenxuan Zhang 5,  Tianlei Li 6,  Song Wu 7
Affiliations

Affiliations

  • 1 Department of Pharmacy, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, China.
  • 2 Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, BMC, Box 596, SE-751 24, Uppsala, Sweden.
  • 3 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 4 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China.
  • 5 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: wxzhang@imm.ac.cn.
  • 6 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: litianlei818@163.com.
  • 7 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: ws@imm.ac.cn.
PMID: 40398156 DOI: 10.1016/j.ejmech.2025.117731
Abstract

Pleuromutilin, a diterpene Fungal metabolite, serves as a privileged scaffold for Antibiotic discovery. Improving its Antibacterial activity and broadening its spectrum remain the primary objectives in developing novel pleuromutilin derivatives. To obtain an ideal candidate, a series of pleuromutilin analogues conjugated to the triphenylphosphonium cation (TPP+) were designed and synthesized. Among them, compound a5 demonstrated enhanced anti-MRSA potency and a broadened Antibacterial spectrum compared to valnemulin and lefamulin, both in vitro and in vivo. Mechanistic studies revealed that a5 disrupted Bacterial membranes and biofilms by elevating intracellular ROS levels-a mechanism distincts from conventional pleuromutilins, which primarily target ribosomal proteins. These findings position a5 as a promising lead compound for developing next-generation broad-spectrum Antibacterial agents.

Keywords

Anti-Gram-negative bacterial activity; Anti-MRSA activity; Pleuromutilin derivatives; Triphenylphosphonium conjugation.

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