2. Academic Validation
  3. Pyrylium derivatives as outer membrane permeabilizers against MDR gram-negative bacteria via multi-target mode of action

Pyrylium derivatives as outer membrane permeabilizers against MDR gram-negative bacteria via multi-target mode of action

  • Eur J Med Chem. 2025 Feb 18:289:117387. doi: 10.1016/j.ejmech.2025.117387.
Qionglu Duan 1,  Min Yuan 2,  Xican Ma 1,  Yifan Zheng 1,  Runze Meng 1,  Wenjing Shi 1,  Yanan Ni 1,  Chen Zhao 3,  Yonghua Liu 1,  Zhihui Yu 1,  Jingyang Zhu 1,  Yulong Shi 1,  Xi Zhu 1,  Li Li 3,  Shuyi Si 1,  Yan Li 4,  Yinghong Li 5,  Danqing Song 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substances and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 2 National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.
  • 3 State Key Laboratory of Bioactive Substances and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 4 State Key Laboratory of Bioactive Substances and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: liyan@imb.pumc.edu.cn.
  • 5 State Key Laboratory of Bioactive Substances and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: liyinghong@imb.pumc.edu.cn.
  • 6 State Key Laboratory of Bioactive Substances and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: songdanqing@imb.pumc.edu.cn.
PMID: 39999691 DOI: 10.1016/j.ejmech.2025.117387
Abstract

The prevalence of MDR Gram-negative bacteria has posed a great impetus for the discovery of new therapeutic approaches. Here, we synthesized a series of pyrylium derivatives as Antibiotic adjuvants based on IMB-0042, and evaluated their activities against Acinetobacter baumannii (A. baumannii) and Escherichia coli (E. coli). Compound 4a significantly synergized polymyxin B in combating A. baumannii and E. coli both in vitro and on the infected Galleria mellonella models. Furthermore, we identified 4a to be an effective perturbant of the Gram-negative outer membrane (OM) through the blockage on LptA/LptC interaction via targeting Met47 in LptA. And cationic pyrylium reduced the OM densification by electrostatic interaction with anion-rich lipopolysaccharide (LPS). Thus, pyrylium derivatives constitute a new class of multi-target OM permeabilizers, which can significantly potentiate Antibiotics against MDR Gram-negative bacteria.

Keywords

LptA/LptC interaction; MDR gram-negative bacteria; Outer membrane permeabilizer; Pyrylium derivatives; Synergistic effect.

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