Paeonol potentiates colistin efficacy against K. pneumoniae by promoting membrane disruption and oxidative damage.
Autor: | Ma C; College of Veterinary Medicine, Qingdao Agricultural University, No.700 Changcheng Road, Qingdao, Shandong 266109, China., Miao QL; College of Veterinary Medicine, Qingdao Agricultural University, No.700 Changcheng Road, Qingdao, Shandong 266109, China., Song XB; Shandong Provincial Key Laboratory of Quality Safety Monitoring and Risk Assessment for Animal Products, Shandong Center for Quality Control of Feed and Veterinary Drug, Jinan 250100, China., Zhao XY; Shandong Provincial Key Laboratory of Quality Safety Monitoring and Risk Assessment for Animal Products, Shandong Center for Quality Control of Feed and Veterinary Drug, Jinan 250100, China., Li YZ; Shandong Provincial Key Laboratory of Quality Safety Monitoring and Risk Assessment for Animal Products, Shandong Center for Quality Control of Feed and Veterinary Drug, Jinan 250100, China., Zou M; College of Veterinary Medicine, Qingdao Agricultural University, No.700 Changcheng Road, Qingdao, Shandong 266109, China., Tang WL; Shandong Provincial Key Laboratory of Quality Safety Monitoring and Risk Assessment for Animal Products, Shandong Center for Quality Control of Feed and Veterinary Drug, Jinan 250100, China. Electronic address: tangwenli2023@163.com., Wu SC; College of Veterinary Medicine, Qingdao Agricultural University, No.700 Changcheng Road, Qingdao, Shandong 266109, China. Electronic address: wushuaicheng10@163.com. |
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Jazyk: | angličtina |
Zdroj: | Phytomedicine : international journal of phytotherapy and phytopharmacology [Phytomedicine] 2024 Dec; Vol. 135, pp. 156061. Date of Electronic Publication: 2024 Sep 16. |
DOI: | 10.1016/j.phymed.2024.156061 |
Abstrakt: | Background: Although colistin is widely recognized as the last line of antibiotics against gram-negative bacteria, the emergence and spread of colistin resistance severely diminish its clinical efficacy and application. An alternative strategy to alleviate this crisis is to identify promising colistin adjuvants with enhanced antibacterial activity. Purpose: In this study, the adjuvant effects of paeonol on colistin and the underlying mechanisms were investigated. Method: Minimum Inhibitory Concentration (MIC) and checkerboard assays were used to investigate the adjuvant activity and structure-activity relationship of paeonol on the antibacterial effect of colistin in vitro. Time-dependent killing and resistance development assays were used to investigate the bactericidal effects and emergence of colistin resistance. Different fluorescent probes and competitive inhibition tests were used to investigate bacterial membrane functions and potential targets. Skin infection and peritonitis-sepsis models were used to evaluate the combined in vivo effects of colistin and paeonol in vivo. Result: Paeonol enhanced the antibacterial effects of colistin against gram-negative bacteria, particularly Klebsiella pneumoniae. Structure-activity relationship analysis showed that the hydroxyl, 4-methoxy and ketone carbonyl side chains of the benzene ring contributed to the adjuvant effect of paeonol. Paeonol enhances the bactericidal effects of colistin and minimizes the emergence of colistin resistance. Notably, mechanistic studies demonstrated that the combination of colistin and paeonol enhances membrane disruption and oxidative damage, possibly via interactions with phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and cardiolipin (CAL). Importantly, paeonol enhanced the efficacy of colistin in both the skin and peritonitis infection models. Conclusion: This is the first report on the adjuvant potential of paeonol in colistin to combat K. pneumoniae by promoting membrane disruption and oxidative damage via targeting membrane phospholipids. Notably, the verified target, PE, provides an additional avenue for screening new colistin adjuvants.The combination therapy of paeonol and colistin is a promising strategy for treating infections caused by gram-negative pathogens to address antibiotic resistance issues. Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, and all authors report no conflicts of interest in this work. (Copyright © 2024. Published by Elsevier GmbH.) |
Databáze: | MEDLINE |
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