Discovery of a novel polymyxin adjuvant against multidrug-resistant gram-negative bacteria through oxidative stress modulation.
10.1016/j.apsb.2025.01.022
- Author:
Taotao LU
1
;
Hongguang HAN
2
;
Chaohui WU
2
;
Qian LI
2
;
Hongyan HU
3
;
Wenwen LIU
2
;
Donglei SHI
2
;
Feifei CHEN
4
;
Lefu LAN
5
;
Jian LI
2
;
Shihao SONG
2
;
Baoli LI
2
Author Information
1. State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
2. Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
3. Hainan Hospital of Chinese PLA General Hospital Laboratory Department, Sanya 5720225, China.
4. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
5. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
- Publication Type:Journal Article
- Keywords:
Adjuvant;
Broad-spectrum synergism;
Drug repurposing;
Gram-negative bacteria;
Multidrug resistance;
Niclosamide;
Oxidative stress;
Polymyxin B
- From:
Acta Pharmaceutica Sinica B
2025;15(3):1680-1695
- CountryChina
- Language:English
-
Abstract:
Antibiotic adjuvants offer a promising strategy for restoring antibiotic sensitivity, expanding antibacterial spectra, and reducing required dosages. Previously, compound 15 was identified as a potential adjuvant for Polymyxin B (PB) against multidrug-resistant (MDR) Pseudomonas aeruginosa DK2; however, its clinical utility was hindered by high cytotoxicity, uncertain in vivo efficacy, and an unclear synergetic mechanism. To address these challenges, we synthesized and evaluated a series of novel benzamide derivatives, with A22 emerging as a particularly promising candidate. A22 demonstrated potent synergistic activity to PB, minimal cytotoxicity, improved water solubility, and broad-spectrum synergism of polymyxins against various clinically isolated MDR Gram-negative strains. In vivo studies using Caenorhabditis elegans and mouse models further confirmed the efficacy of A22. Moreover, A22 effectively suppressed the development of PB resistance in Pseudomonas aeruginosa DK2. Mechanistic investigations revealed that A22 enhances polymyxins activity by inducing reactive oxygen species production, reducing ATP levels, increasing NOX activity, and inhibiting biofilm formation, leading to bacterial death. These findings position A22 as a highly promising candidate for the development of polymyxin adjuvants, offering a robust approach to combating MDR Gram-negative bacterial infections.
