Repurposing fenticonazole nitrate to restore colistin susceptibility in multidrug-resistant bacteria.

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Life sciences Pub Date : 2025-03-02 DOI:10.1016/j.lfs.2025.123511

Yueyue Ji, Chenchen Wang, Hongjiang Lai, Xiaodan Li, Zhaoran Zhang, Xiangru Wang, Huanchun Chen, Chen Tan

{"title":"Repurposing fenticonazole nitrate to restore colistin susceptibility in multidrug-resistant bacteria.","authors":"Yueyue Ji, Chenchen Wang, Hongjiang Lai, Xiaodan Li, Zhaoran Zhang, Xiangru Wang, Huanchun Chen, Chen Tan","doi":"10.1016/j.lfs.2025.123511","DOIUrl":null,"url":null,"abstract":"Aims: To explore the synergistic effect of the combination of FN and colistin on Escherichia coli and further elucidate the mechanism of this effect.Main methods: Antimicrobial efficacy of the combination of fenticonazole nitrate and colistin against Escherichia coli in vitro using MIC assays, checkerboard assays, growth curves, and time-kill curves. Crystalline violet staining for detection of biofilm. Mechanisms analysis using fluorescence detection, SEM. Analysis of fenticonazole nitrate and MCR-1 interaction using molecular docking and ITC. Finally, the efficacy of combination therapy for MCR-1-positive Escherichia coli was assessed in vivo.Key findings: Fenticonazole nitrate significantly enhanced the ability of colistin to combat mcr-1-positive E. coli 42 in vitro. The combination could effectively inhibit biofilm formation and eradicate established biofilms. Fenticonazole nitrate and colistin could increase the outer membrane permeability of E. coli 42, disrupting the membrane potential and impairing PMF synthesis, which in turn led to a reduction in ATP levels and cell death. Further, we found that the outer membrane barrier of Gram-negative bacteria and the innate resistance mechanism mediated by efflux pumps can impair the antimicrobial activity of fenticonazole nitrate. Finally, the combination demonstrated strong synergistic effects in a mouse model of infection with mcr-1-positive E. coli 42. Compared to the colistin only group, the survival rate increased by 40 %.Conclusion: Fenticonazole nitrate is a promising antibiotic adjuvant against infections caused by MCR-1-positive multidrug-resistant pathogens.","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":" ","pages":"123511"},"PeriodicalIF":5.2000,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Life sciences","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.lfs.2025.123511","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}

引用次数: 0

Abstract

Aims: To explore the synergistic effect of the combination of FN and colistin on Escherichia coli and further elucidate the mechanism of this effect.

Main methods: Antimicrobial efficacy of the combination of fenticonazole nitrate and colistin against Escherichia coli in vitro using MIC assays, checkerboard assays, growth curves, and time-kill curves. Crystalline violet staining for detection of biofilm. Mechanisms analysis using fluorescence detection, SEM. Analysis of fenticonazole nitrate and MCR-1 interaction using molecular docking and ITC. Finally, the efficacy of combination therapy for MCR-1-positive Escherichia coli was assessed in vivo.

Key findings: Fenticonazole nitrate significantly enhanced the ability of colistin to combat mcr-1-positive E. coli 42 in vitro. The combination could effectively inhibit biofilm formation and eradicate established biofilms. Fenticonazole nitrate and colistin could increase the outer membrane permeability of E. coli 42, disrupting the membrane potential and impairing PMF synthesis, which in turn led to a reduction in ATP levels and cell death. Further, we found that the outer membrane barrier of Gram-negative bacteria and the innate resistance mechanism mediated by efflux pumps can impair the antimicrobial activity of fenticonazole nitrate. Finally, the combination demonstrated strong synergistic effects in a mouse model of infection with mcr-1-positive E. coli 42. Compared to the colistin only group, the survival rate increased by 40 %.

Conclusion: Fenticonazole nitrate is a promising antibiotic adjuvant against infections caused by MCR-1-positive multidrug-resistant pathogens.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

求助全文

约1分钟内获得全文去求助

来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.