Anticandidal Effect and Mechanisms of Monoterpenoid, Perillyl Alcohol against Candida albicans.
Anticandidal Effect and Mechanisms of Monoterpenoid, Perillyl Alcohol against Candida albicans.
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DOI：
10.1371/journal.pone.0162465
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Hameed S
中科院分区：
文献类型：
--
作者：
Ansari MA;Fatima Z;Hameed S
本研究探讨了紫苏醇(PA)对人类最常见的真菌病原菌白色念珠菌及其临床分离株和4种非白色念珠菌的抗真菌活性。为了解决可能的机制，我们使用PA处理的念珠菌细胞的全基因组转录组分析来检测这种病原体受影响的细胞电路。转录组数据显示，在几类PA反应基因中，钙调神经磷酸酶信号与PA有关联，其中钙调神经磷酸酶信号基因CNB1的下调值得注意，分子对接和敏感性分析也证实了这一点。我们观察到，PA处理的念珠菌抑制了钙调神经磷酸酶途径的应激反应，并对碱性pH、离子、膜、盐度、内质网和血清应激反应变得敏感。进一步证实了功能钙调神经磷酸酶的必要性，因为钙调神经磷酸酶突变株对PA高度敏感，而结构性表达的钙调神经磷酸酶菌株仍具有抗性。我们探索了PA导致膜完整性被扰乱，通过耗尽麦角甾醇水平和破坏pH动态平衡来描述。此外，PA还引起细胞壁损伤，表现为对细胞壁扰动剂(刚果红、钙粉白)的超敏反应、扫描电子显微镜和细胞沉降率增加。此外，PA抑制了潜在的毒力特征，包括形态转变、生物膜的形成，并显示出与聚苯乙烯表面和口腔上皮细胞的黏附能力减弱。研究还显示，PA会导致白念珠菌细胞周期停滞和线粒体功能障碍。总之，本研究为进一步研究PA提供了足够的证据，以便采用更好的策略来治疗念珠菌感染。
This study explored the antifungal potential of perillyl alcohol (PA), a natural monoterpene alcohol, against most prevalent human fungal pathogen C. albicans, its clinical isolates and four non-albicans species of Candida. To resolve the potential mechanisms, we used whole genome transcriptome analyses of PA treated Candida cells to examine the affected cellular circuitry of this pathogen. The transcriptome data revealed a link between calcineurin signaling and PA as among the several categories of PA responsive genes the down regulation of calcineurin signaling gene CNB1 was noteworthy which was also confirmed by both molecular docking and susceptibility assays. We observed that PA treated Candida phenocopied compromised calcineurin pathway stress responses and turned sensitive to alkaline pH, ionic, membrane, salinity, endoplasmic reticulum and serum stresses. Indispensability of functional calcineurin was further confirmed as calcineurin mutant was hypersensitive to PA while constitutively expressed calcineurin strain remained resistant. We explored that PA leads to perturbed membrane integrity as depicted through depleted ergosterol levels and disrupted pH homeostasis. Moreover, PA caused cell wall damage which was evident from hypersensitivity against cell wall perturbing agents (congo red, calcoflour white), SEM and enhanced rate of cell sedimentation. Furthermore, PA inhibited potential virulence traits including morphological transition, biofilm formation and displayed diminished capacity to adhere both to the polystyrene surface and buccal epithelial cells. The study also revealed that PA leads to cell cycle arrest and mitochondrial dysfunction in C. albicans. Together, the present study provides enough evidence for further work on PA so that better strategies could be employed to treat Candida infections.
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