{"title":"Synergistic antifungal effects and mechanisms of amantadine hydrochloride combined with azole antifungal drugs on drug-resistant <i>Candida albicans</i>.","authors":"Xiuyun Li, Yuanyuan Zhi, Ximeng Duan, Xu Chen, Min Cui, Shicun Zheng","doi":"10.3389/fcimb.2025.1455123","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>The increasing resistance of <i>Candida albicans</i> (<i>C. albicans</i>) to conventional antifungal drugs poses a great challenge to the clinical treatment of infections caused by this yeast. Drug combinations are a potential therapeutic approach to overcome the drug- resistance of <i>C. albicans</i>. This study explored the synergistic effects of amantadine hydrochloride (AMH) combined with azole antifungal drugs against drug-resistant <i>C. albicans in vitro</i> and <i>in vivo</i>.</p><p><strong>Methods: </strong>The <i>in vitro</i> sensitivity of <i>Candida</i> spp. to drugs was determined by the microdilution method. The effect of drugs on the efflux pump activity of <i>C. albicans</i> was determined by the rhodamine 6G tracer method. The egg yolk agar plate method was used to determine the activity of extracellular phospholipase, a <i>C. albicans</i> virulence factor. The <i>Galleria mellonella</i> model of <i>C. albicans</i> infection was used to test the <i>in vivo</i> efficacy of the combination therapy.</p><p><strong>Results: </strong><i>In vitro</i> experiments showed that combinations of AMH with azole antifungal drugs had synergistic antifungal effects on planktonic cells of drug-resistant <i>C. albicans</i>, with fractional inhibitory concentration index values of <0.5. The <i>in vivo</i> synergistic effects and mechanism of drug combinations with AMH were further studied using fluconazole (FLC) as a representative azole antifungal drug. <i>In vivo</i>, <i>G. mellonella</i> larvae were used to evaluate the antifungal efficacy of AMH +FLC. AMH + FLC treatment increased the survival rate of larvae infected with drug-resistant <i>C. albicans</i> and reduced tissue invasion. Studies of the mechanism of synergy showed that AMH inhibited drug efflux pump activity in drug-resistant <i>C. albicans</i>, and that AMH + FLC synergistically inhibited early biofilms and the extracellular phospholipase activity of drug-resistant <i>C. albicans</i>.</p><p><strong>Conclusion: </strong>This study provides strong evidence that combinations of non-antifungal drugs and antifungal drugs can effectively overcome drug-resistant <i>C. albicans</i> infection. Both AMH and FLC are FDA-approved drugs, eliminating concerns about safety. Our findings provide a foundation for further clinical antifungal research.</p>","PeriodicalId":12458,"journal":{"name":"Frontiers in Cellular and Infection Microbiology","volume":"15 ","pages":"1455123"},"PeriodicalIF":4.6000,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897512/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in Cellular and Infection Microbiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3389/fcimb.2025.1455123","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Introduction: The increasing resistance of Candida albicans (C. albicans) to conventional antifungal drugs poses a great challenge to the clinical treatment of infections caused by this yeast. Drug combinations are a potential therapeutic approach to overcome the drug- resistance of C. albicans. This study explored the synergistic effects of amantadine hydrochloride (AMH) combined with azole antifungal drugs against drug-resistant C. albicans in vitro and in vivo.
Methods: The in vitro sensitivity of Candida spp. to drugs was determined by the microdilution method. The effect of drugs on the efflux pump activity of C. albicans was determined by the rhodamine 6G tracer method. The egg yolk agar plate method was used to determine the activity of extracellular phospholipase, a C. albicans virulence factor. The Galleria mellonella model of C. albicans infection was used to test the in vivo efficacy of the combination therapy.
Results: In vitro experiments showed that combinations of AMH with azole antifungal drugs had synergistic antifungal effects on planktonic cells of drug-resistant C. albicans, with fractional inhibitory concentration index values of <0.5. The in vivo synergistic effects and mechanism of drug combinations with AMH were further studied using fluconazole (FLC) as a representative azole antifungal drug. In vivo, G. mellonella larvae were used to evaluate the antifungal efficacy of AMH +FLC. AMH + FLC treatment increased the survival rate of larvae infected with drug-resistant C. albicans and reduced tissue invasion. Studies of the mechanism of synergy showed that AMH inhibited drug efflux pump activity in drug-resistant C. albicans, and that AMH + FLC synergistically inhibited early biofilms and the extracellular phospholipase activity of drug-resistant C. albicans.
Conclusion: This study provides strong evidence that combinations of non-antifungal drugs and antifungal drugs can effectively overcome drug-resistant C. albicans infection. Both AMH and FLC are FDA-approved drugs, eliminating concerns about safety. Our findings provide a foundation for further clinical antifungal research.
期刊介绍：
Frontiers in Cellular and Infection Microbiology is a leading specialty journal, publishing rigorously peer-reviewed research across all pathogenic microorganisms and their interaction with their hosts. Chief Editor Yousef Abu Kwaik, University of Louisville is supported by an outstanding Editorial Board of international experts. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.
Frontiers in Cellular and Infection Microbiology includes research on bacteria, fungi, parasites, viruses, endosymbionts, prions and all microbial pathogens as well as the microbiota and its effect on health and disease in various hosts. The research approaches include molecular microbiology, cellular microbiology, gene regulation, proteomics, signal transduction, pathogenic evolution, genomics, structural biology, and virulence factors as well as model hosts. Areas of research to counteract infectious agents by the host include the host innate and adaptive immune responses as well as metabolic restrictions to various pathogenic microorganisms, vaccine design and development against various pathogenic microorganisms, and the mechanisms of antibiotic resistance and its countermeasures.
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