Hinokitiol chelates intracellular iron to retard fungal growth by disturbing mitochondrial respiration.
Hinokitiol chelates intracellular iron to retard fungal growth by disturbing mitochondrial respiration.
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扁柏酚螯合细胞内铁，通过干扰线粒体呼吸来抑制真菌生长
DOI：
10.1016/j.jare.2021.06.016
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发表时间：
2021-12
影响因子：
10.7
通讯作者：
Lou H
中科院分区：
文献类型：
--
作者：
Jin X;Zhang M;Lu J;Duan X;Chen J;Liu Y;Chang W;Lou H
真菌感染发病率的增加和耐药性的普遍存在突出了新的抗真菌药物的发现和其作用方式的研究。铁螯合剂已被用于治疗浅表真菌感染或增强某些抗真菌药物的功效。桧木醇具有较强的抗真菌活性和铁螯合能力。然而，他们的关系还没有建立起来。本研究旨在探讨桧木醇对真菌细胞和哺乳动物细胞的选择性，并确定铁螯合对桧木醇抗真菌活性的作用。铁探针FeRhonox-1测定细胞内Fe2+含量。采用5-氰-2,3-二醇四氮氯化铵探针和细胞计数试剂盒-8检测线粒体呼吸活动。采用实时荧光定量PCR和救援实验研究了铁对桧木醇抗真菌活性的影响。利用活性氧探针和几种商业检测试剂盒进一步评估了扁柏醇对真菌线粒体的影响。采用串联传代法研究了桧木醇对念珠菌的抗性诱导能力。以mellongalleria为感染模型，评价了桧木醇的体内治疗效果。桧木醇对一组具有多重唑耐药机制的念珠菌菌株有效，并持续抑制白色念珠菌的生长。机制研究表明，桧木醇螯合真菌细胞内铁，抑制真菌细胞的呼吸，但对哺乳动物细胞的影响较小。桧木醇进一步抑制线粒体呼吸链复合物I和II的活性，降低线粒体膜电位，从而减少细胞内ATP合成，增加有害的细胞内还原应激。此外，桧木醇在几种念珠菌中表现出较低的抗性诱导潜力，并大大提高了感染念珠菌的mellongalleria的存活率。这些发现提示了扁柏醇作为铁螯合剂治疗真菌感染的潜在应用前景。
The increasing morbidity of fungal infections and the prevalence of drug resistance highlighted the discovery of novel antifungal agents and investigation of their modes of action. Iron chelators have been used to treat superficial fungal infections or potentiate the efficacy of certain antifungal drugs. Hinokitiol exhibits potent antifungal activity and iron-chelating ability. However, their relationships have not been established. This study aims to explore the selectivity of hinokitiol against fungal cells and mammalian cells and determine the role of iron-chelating for the antifungal activity of hinokitiol. Iron probe FeRhonox-1 was used to determine intracellular Fe2+ content. 5-Cyano-2,3-ditolyl tetrazolium chloride probe and Cell Counting Kit-8 were used to detect the mitochondrial respiratory activities. Quantitative real-time PCR and rescue experiments were performed to determine the effect of iron on the antifungal activity of hinokitiol. The effects of hinokitiol on fungal mitochondria were further evaluated using reactive oxygen species probes and several commercial Assay Kits. The ability of hinokitiol to induce resistance in Candida species was carried out using a serial passage method. The in vivo therapeutic effect of hinokitiol was evaluated using Galleria mellonella as an infectious model. Hinokitiol was effective against a panel of Candida strains with multiple azole-resistant mechanisms and persistently inhibited Candida albicans growth. Mechanism investigations revealed that hinokitiol chelated fungal intracellular iron and inhibited the respiration of fungal cells but had minor effects on mammalian cells. Hinokitiol further inhibited the activities of mitochondrial respiratory chain complexes I and II and reduced mitochondrial membrane potential, thereby decreasing intracellular ATP synthesis and increasing detrimental intracellular reductive stress. Moreover, hinokitiol exhibited low potential for inducing resistance in several Candida species and greatly improved the survival of Candida-infected Galleria mellonella. These findings suggested the potential application of hinokitiol as an iron chelator to treat fungal infections.
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影响因子：
3.7
作者：
Kim DJ;Lee MW;Choi JS;Lee SG;Park JY;Kim SW
通讯作者：
Kim SW
影响因子：
5.7
作者：
Li Y;Sun L;Lu C;Gong Y;Li M;Sun S
通讯作者：
Sun S
影响因子：
6.4
作者：
Arendrup, Maiken Cavling;Patterson, Thomas F.
通讯作者：
Patterson, Thomas F.
G.梅洛尼菌幼虫的标准化在真菌病原体的研究中提供可靠且可重复的结果。
DOI：
10.3390/jof4030108
发表时间：
2018-09-06
期刊：
Journal of fungi (Basel, Switzerland)
影响因子：
--
作者：
Champion OL;Titball RW;Bates S
通讯作者：
Bates S
影响因子：
6.7
作者：
Grahl N;Demers EG;Lindsay AK;Harty CE;Willger SD;Piispanen AE;Hogan DA
通讯作者：
Hogan DA