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

被引：0

作者：

Duan, Qionglu ^{[1
]}

Yuan, Min ^{[2
]}

Ma, Xican ^{[1
]}

Zheng, Yifan ^{[1
]}

Meng, Runze ^{[1
]}

Shi, Wenjing ^{[1
]}

Ni, Yanan ^{[1
]}

Zhao, Chen ^{[3
]}

Liu, Yonghua ^{[1
]}

Yu, Zhihui ^{[1
]}

Zhu, Jingyang ^{[1
]}

Shi, Yulong ^{[1
]}

Zhu, Xi ^{[1
]}

Li, Li ^{[3
]}

Si, Shuyi ^{[1
]}

Li, Yan ^{[1
]}

Li, Yinghong ^{[1
]}

Song, Danqing ^{[1
]}

机构：

[1] Chinese Acad Med Sci & Peking Union Med Coll, Inst Med Biotechnol, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China

[2] Chinese Ctr Dis Control & Prevent, Natl Inst Communicable Dis Control & Prevent, Natl Key Lab Intelligent Tracking & Forecasting In, Beijing 102206, Peoples R China

[3] Chinese Acad Med Sci & Peking Union Med Coll, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2025年 / 289卷

关键词：

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

D O I：

10.1016/j.ejmech.2025.117387

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 Gramnegative 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.

引用

页数：12

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