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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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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