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Discovery of a novel polymyxin adjuvant against multidrug-resistant gram-negative bacteria through oxidative stress modulation

文献类型：期刊论文

作者Lu, Taotao8; Han, Hongguang1,2; Wu, Chaohui1,2; Li, Qian1,2; Hu, Hongyan7; Liu, Wenwen1,2; Shi, Donglei1,2; Chen, Feifei5,6; Lan, Lefu4,5; Li, Jian1,2,3,8
刊名ACTA PHARMACEUTICA SINICA B
出版日期2025-03-01
卷号15期号:3页码:1680-1695
关键词Multidrug resistance Gram-negative bacteria Niclosamide Drug repurposing Polymyxin B Adjuvant Broad-spectrum synergism Oxidative stress
ISSN号2211-3835
DOI10.1016/j.apsb.2025.01.022
通讯作者Li, Jian(jianli@ecust.edu.cn) ; Song, Shihao(songsh@hainanu.edu.cn) ; Li, Baoli(baolili@hainanu.edu.cn)
英文摘要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.
2025 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
WOS关键词PSEUDOMONAS-AERUGINOSA ; ANTIBIOTIC ADJUVANTS ; ATP
资助项目National Natural Science Foundation of China[22107023] ; National Natural Science Foundation of China[32300033] ; Natural Science Foundation of Hainan[222QN220] ; Scientific Research Foundation of Hainan University[22010] ; Scientific Research Foundation of Hainan University[23006]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001464755400001
出版者INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/317425]  
专题中国科学院上海药物研究所
通讯作者Li, Jian; Song, Shihao; Li, Baoli
作者单位1.Hainan Univ, Hainan Engn Res Ctr Drug Screening & Evaluat, Sch Pharmaceut Sci, Haikou 570228, Peoples R China
2.Hainan Univ, Sch Pharmaceut Sci, Key Lab Trop Biol Resources, Minist Educ, Haikou 570228, Peoples R China
3.Shihezi Univ, Sch Pharm, Key Lab Xinjiang Phytomed Resource & Utilizat, Minist Educ, Shihezi 832003, Peoples R China
4.Anhui Med Univ, Affiliated Hosp 1, Anhui Prov Key Lab Infect Dis, Hefei 230022, Peoples R China
5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
7.Hainan Hosp, Chinese PLA Gen Hosp Lab Dept, Sanya, Peoples R China
8.East China Univ Sci & Technol, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Frontiers Sci Ctr Materiobiol & Dynam Chem, Sch Pharm,State Key Lab Bioreactor Engn,Shanghai K, Shanghai 200237, Peoples R China
推荐引用方式
GB/T 7714		 Lu, Taotao,Han, Hongguang,Wu, Chaohui,et al. Discovery of a novel polymyxin adjuvant against multidrug-resistant gram-negative bacteria through oxidative stress modulation[J]. ACTA PHARMACEUTICA SINICA B,2025,15(3):1680-1695.
APA Lu, Taotao.,Han, Hongguang.,Wu, Chaohui.,Li, Qian.,Hu, Hongyan.,...&Li, Baoli.(2025).Discovery of a novel polymyxin adjuvant against multidrug-resistant gram-negative bacteria through oxidative stress modulation.ACTA PHARMACEUTICA SINICA B,15(3),1680-1695.
MLA Lu, Taotao,et al."Discovery of a novel polymyxin adjuvant against multidrug-resistant gram-negative bacteria through oxidative stress modulation".ACTA PHARMACEUTICA SINICA B 15.3(2025):1680-1695.

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来源：上海药物研究所

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