{"title":"Antifungal activity of Cinnamaldehyde derivatives against fluconazole-resistant Candida albicans","authors":"","doi":"10.1016/j.micpath.2024.106877","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p><em>Candida albicans</em> is an opportunistic pathogen commonly found in human mucous membranes. In light of the escalating challenge posed by antibiotic resistance of <em>C. albicans</em> strains worldwide, it is an urgently necessary to explore alternative therapeutic options.</p></div><div><h3>Objective</h3><p>This study aims to assess the efficacy of two Cinnamaldehyde derivatives, 2-Cl Cinnamaldehyde (2-Cl CA) and 4-Cl Cinnamaldehyde (4-Cl CA), against <em>C. albicans</em> through both <em>in vitro</em> experiments and <em>in vivo</em> murine models and to evaluate their potential as new drug candidates for treating <em>C. albicans</em>.</p></div><div><h3>Methods and results</h3><p>The minimum inhibitory concentrations (MICs) of Cinnamaldehyde 2-Cl and 4-Cl benzene ring derivatives against <em>C. albicans</em> were 25 μg/mL. Time-killing experiments revealed that both Cinnamaldehyde derivatives exhibited fungicidal activity against <em>C. albicans</em> at concentrations of 5 MIC and 10 MIC. In the checkerboard experiment, 4-Cl CA did not show any antagonistic effect when combined with first-line antifungal drugs. Instead, it exhibited additive effects in combination with nystatin. Both 2-Cl and 4-Cl CA demonstrated inhibitory activity against <em>C. albicans</em> biofilm formation, especially at 8 MIC and 16 MIC concentrations. In <em>C. albicans</em> biofilm eradication experiments, although high drug concentrations of 2-Cl and 4-Cl CA were unable to eradicate the biofilm completely, they were still effective in killing <em>C. albicans</em> cells within the biofilm. Moreover, sub-inhibitory concentrations of 4-Cl CA (ranging from 5 to 20 μg/mL) significantly inhibited cell aggregation and hyphal formation. Furthermore, 4-Cl CA effectively inhibited intracellular <em>C. albicans</em> infection in macrophages. Lastly, the effectiveness of 4-Cl CA was evaluated in a mouse model of hematogenous disseminated candidiasis caused by <em>C. albicans</em>, which revealed that 4-Cl CA significantly reduced fungal burden and improved mouse survival compared to the untreated controls.</p></div><div><h3>Conclusion</h3><p>The 4-Cl CA exhibited inhibitory effects against <em>C. albicans</em> through both <em>in vivo</em> and <em>in vitro</em> models, demonstrating its therapeutic potential as a promising new drug candidate for treating drug-resistant candidiasis albicans.</p></div>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Microbial pathogenesis","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0882401024003449","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background
Candida albicans is an opportunistic pathogen commonly found in human mucous membranes. In light of the escalating challenge posed by antibiotic resistance of C. albicans strains worldwide, it is an urgently necessary to explore alternative therapeutic options.
Objective
This study aims to assess the efficacy of two Cinnamaldehyde derivatives, 2-Cl Cinnamaldehyde (2-Cl CA) and 4-Cl Cinnamaldehyde (4-Cl CA), against C. albicans through both in vitro experiments and in vivo murine models and to evaluate their potential as new drug candidates for treating C. albicans.
Methods and results
The minimum inhibitory concentrations (MICs) of Cinnamaldehyde 2-Cl and 4-Cl benzene ring derivatives against C. albicans were 25 μg/mL. Time-killing experiments revealed that both Cinnamaldehyde derivatives exhibited fungicidal activity against C. albicans at concentrations of 5 MIC and 10 MIC. In the checkerboard experiment, 4-Cl CA did not show any antagonistic effect when combined with first-line antifungal drugs. Instead, it exhibited additive effects in combination with nystatin. Both 2-Cl and 4-Cl CA demonstrated inhibitory activity against C. albicans biofilm formation, especially at 8 MIC and 16 MIC concentrations. In C. albicans biofilm eradication experiments, although high drug concentrations of 2-Cl and 4-Cl CA were unable to eradicate the biofilm completely, they were still effective in killing C. albicans cells within the biofilm. Moreover, sub-inhibitory concentrations of 4-Cl CA (ranging from 5 to 20 μg/mL) significantly inhibited cell aggregation and hyphal formation. Furthermore, 4-Cl CA effectively inhibited intracellular C. albicans infection in macrophages. Lastly, the effectiveness of 4-Cl CA was evaluated in a mouse model of hematogenous disseminated candidiasis caused by C. albicans, which revealed that 4-Cl CA significantly reduced fungal burden and improved mouse survival compared to the untreated controls.
Conclusion
The 4-Cl CA exhibited inhibitory effects against C. albicans through both in vivo and in vitro models, demonstrating its therapeutic potential as a promising new drug candidate for treating drug-resistant candidiasis albicans.
背景:白色念珠菌是一种常见于人体粘膜的机会性病原体。鉴于全球范围内白色念珠菌菌株对抗生素的耐药性所带来的挑战不断升级,迫切需要探索其他治疗方案:本研究旨在通过体外实验和体内小鼠模型评估两种肉桂醛衍生物--2-氯肉桂醛(2-Cl CA)和 4-氯肉桂醛(4-Cl CA)对白僵菌的疗效,并评估它们作为治疗白僵菌新药候选物的潜力:肉桂醛 2-Cl 和 4-Cl 苯环衍生物对白茨球菌的最低抑制浓度(MICs)为 25 μg/mL。杀菌时间实验表明,肉桂醛衍生物在 5 MIC 和 10 MIC 浓度下对白僵菌都具有杀菌活性。在棋盘实验中,4-Cl CA 与一线抗真菌药物联用时未显示出任何拮抗作用。相反,它与硝司他丁合用时却显示出了相加效应。2-Cl 和 4-Cl CA 对白僵菌生物膜的形成都有抑制作用,尤其是在 8 MIC 和 16 MIC 浓度下。在消灭白僵菌生物膜的实验中,虽然高浓度的 2-Cl 和 4-Cl CA 无法完全消灭生物膜,但仍能有效杀死生物膜内的白僵菌细胞。此外,亚抑制浓度的 4-Cl CA(5 至 20 μg/mL)能显著抑制细胞聚集和菌丝形成。此外,4-Cl CA 还能有效抑制巨噬细胞内的白僵菌感染。最后,在由白念珠菌引起的血源性播散性念珠菌病小鼠模型中评估了 4-Cl CA 的有效性,结果显示,与未经处理的对照组相比,4-Cl CA 能明显减轻真菌负担,提高小鼠存活率:结论:4-Cl CA 在体内和体外模型中都表现出了对白念珠菌的抑制作用,证明了其作为治疗耐药白念珠菌的候选新药的治疗潜力。
期刊介绍:
Microbial Pathogenesis publishes original contributions and reviews about the molecular and cellular mechanisms of infectious diseases. It covers microbiology, host-pathogen interaction and immunology related to infectious agents, including bacteria, fungi, viruses and protozoa. It also accepts papers in the field of clinical microbiology, with the exception of case reports.
Research Areas Include:
-Pathogenesis
-Virulence factors
-Host susceptibility or resistance
-Immune mechanisms
-Identification, cloning and sequencing of relevant genes
-Genetic studies
-Viruses, prokaryotic organisms and protozoa
-Microbiota
-Systems biology related to infectious diseases
-Targets for vaccine design (pre-clinical studies)