AI Article Synopsis
- Colistin, often used as the last-resort antibiotic against gram-negative bacteria, faces efficacy challenges due to rising resistance, prompting the search for effective adjuvants like paeonol.
- This study assessed the synergistic effects of paeonol on colistin’s antibacterial activity through various assays and in vivo models, revealing that paeonol significantly enhances colistin's effectiveness, particularly against Klebsiella pneumoniae.
- The research identified specific structural components of paeonol that contribute to this adjuvant effect and suggested that the combination increases membrane disruption and oxidative damage in bacteria, while also reducing colistin resistance development.
Article Abstract
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.
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| http://dx.doi.org/10.1016/j.phymed.2024.156061 | DOI Listing |
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