更新于：2024-11-01

Ergosterol x CYP51A1

更新于：2024-11-01

基本信息

关联

项与 Ergosterol x CYP51A1 相关的药物

Naftifine hydrochloride/Ketoconazole

萘替芬酮康唑

靶点

CYP51A1 x Ergosterol

作用机制

CYP51A1抑制剂 [+1]

在研机构

重庆华邦制药有限公司

原研机构

重庆华邦制药有限公司

在研适应症

真菌病

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区

中国

首次获批日期2005-09-26

100 项与 Ergosterol x CYP51A1 相关的临床结果

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100 项与 Ergosterol x CYP51A1 相关的转化医学

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0 项与 Ergosterol x CYP51A1 相关的专利（医药）

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项与 Ergosterol x CYP51A1 相关的文献（医药）

2024-09-01·Microbiological Research

Deciphering the mechanisms involved in reduced sensitivity to azoles and fengycin lipopeptide in Venturia inaequalis

Article

作者: Deleu, Magali ; Duban, Matthieu ; Hoste, Alexis ; Lounès-Hadj Sahraoui, Anissa ; Compère, Philippe ; Deweer, Caroline ; Coutte, François ; Sahmer, Karin ; Muchembled, Jérôme ; Siah, Ali ; Jacques, Philippe ; Trapet, Pauline ; Fiévet, Valentin ; Farce, Amaury ; Laruelle, Frédéric ; Jacquin, Justine ; Leconte, Aline

Apple scab, caused by the hemibiotrophic fungus Venturia inaequalis, is currently the most common and damaging disease in apple orchards. Two strains of V. inaequalis (S755 and Rs552) with different sensitivities to azole fungicides and the bacterial metabolite fengycin were compared to determine the mechanisms responsible for these differences. Antifungal activity tests showed that Rs552 had reduced sensitivity to tebuconazole and tetraconazole, as well as to fengycin alone or in a binary mixture with other lipopeptides (iturin A, pumilacidin, lichenysin). S755 was highly sensitive to fengycin, whose activity was close to that of tebuconazole. Unlike fengycin, lipopeptides from the iturin family (mycosubtilin, iturin A) had similar activity on both strains, while those from the surfactin family (lichenysin, pumilacidin) were not active, except in binary mixtures with fengycin. The activity of lipopeptides varies according to their family and structure. Analyses to determine the difference in sensitivity to azoles (which target the CYP51 enzyme involved in the ergosterol biosynthesis pathway) showed that the reduced sensitivity in Rs552 is linked to (i) a constitutive increased expression of the Cyp51A gene caused by insertions in the upstream region and (ii) greater efflux by membrane pumps with the involvement of ABC transporters. Microscopic observations revealed that fengycin, known to interact with plasma membranes, induced morphological and cytological changes in cells from both strains. Sterol and phospholipid analyses showed a higher level of ergosta-7,22-dien-3-ol and a lower level of PI(C16:0/C18:1) in Rs552 compared with S755. These differences could therefore influence the composition of the plasma membrane and explain the differential sensitivity of the strains to fengycin. However, the similar antifungal activities of mycosubtilin and iturin A in the two strains indirectly indicate that sterols are probably not involved in the fengycin resistance mechanism. This leads to the conclusion that different mechanisms are responsible for the difference in susceptibility to azoles or fengycin in the strains studied.

2022-12-01·World Journal of Microbiology and Biotechnology

Thidiazuron, a phenyl-urea cytokinin, inhibits ergosterol synthesis and attenuates biofilm formation of Candida albicans

Article

作者: Thirugnanasambantham, Krishnaraj ; Jayaraman, Vijay Karthik ; Ibrahim, Hairul-Islam Mohamed ; Harikrishnan, Pandurangan ; Sundaresan, Arjunan ; Senthilkumar, Palanisamy ; Ahmed, Emad A ; Ekambaram, Kanimozhi ; Arayambath, Balamani

Candida albicans is a common human fungal pathogen that colonizes mucosa and develops biofilm in the oral cavity that causes oral candidiasis. It has been reported that cytochrome P450 enzyme (CYP51), a vital part of the ergosterol synthesis cascade, is associated with Candida infections and its biofilm formation. Thidiazuron, a phenyl-urea cytokinin, exhibits anti-senescence and elicitor activity against fungal infection in plants. However, how Thidiazuron impacts C. albicans biofilm formation is still uncertain. Here, we aimed to investigate the effects of a Thidiazuron against the growth and biofilm formation properties of C. albicans using in silico and in vitro experimental approaches. A preliminary molecular docking study revealed potential interaction between Thidiazuron and amino acid residues of CYP51. Further in vitro antifungal susceptibility test, scanning electron microscopy (SEM) and time kill analysis revealed the anti-fungal activity of Thidiazuron in both dose and time-dependent manner. Crystal violet staining, 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assay revealed 50% inhibition in C. albicans biofilm by Thidiazuron at concentrations 11 and 19 µM respectively. Acridine orange staining assay visually confirmed the biofilm inhibitory potential of Thidiazuron. The gene expression study showed that Thidiazuron treatment down regulated the expression of genes involved in ergosterol synthesis (ERG3, ERG11, ERG25), cell adhesion (ASL3, EAP1), and hyphae development (EFG1, HWP1, SAP5) in C. albicans. Wherease, the expression of negative transcription regulator of hyphae (NRG1) was upregulated (5.7-fold) by Thidiazuron treatment. Collectively, our data suggest that Thidiazuron is a robust antifungal compound and an outstanding biofilm inhibitor, which may promise further therapeutic development due to CYP51 binding and inhibition of ergosterol formation against C. albicans.

2021-09-03·Medical Mycology3区 · 医学

Characterization ofProtothecaCYP51/ERG11 as a possible target for therapeutic drugs

3区 · 医学

Article

作者: Matsumura, Kaori ; Ishikawa, Tomohiro ; Watanabe, Takahisa ; Nishimura, Kazuko ; Sato, Hirotaka ; Masuda, Michiaki ; Hirose, Noriyuki ; Masubuchi, Akira ; Nonaka, Lisa

AbstractPrototheca spp. are achlorophyllous algae, ubiquitous in nature. An increasing number of human and animal cases of Prototheca infection (protothecosis) are reported, and antifungal azoles, which inhibit sterol 14α-demethylase (CYP51/ERG11) involved in ergosterol biosynthesis, have empirically been used for the treatment of protothecosis. Although Prototheca, like fungi, has ergosterol in the cell membrane, efficacy of the antifungal azoles in the treatment of protothecosis is controversial. For investigating the interaction of azole drugs with Prototheca CYP51/ERG11, the CYP51/ERG11 genomic genes of four strains of P. wickerhamii and one strain each of P. cutis and P. miyajii were isolated and characterized in this study. Compared with the CYP51/ERG11 gene of chlorophyllous Auxenochlorella Protothecoides, it is possible that ProtothecaCYP51/ERG11 gene, whose exon-intron structure appeared to be species-specific, lost introns associated with the loss of photosynthetic activity. Analysis of the deduced amino acid sequences revealed that Prototheca CYP51/ERG11 and fungal CYP51/ERG11 are phylogenetically distant from each other although their overall structures are similar. Our basic in silico studies predicted that antifungal azoles could bind to the catalytic pocket of Prototheca CYP51/ERG11. It was also suggested that amino acid residues away from the catalytic pocket might affect the drug susceptibility. The results of this study may provide useful insights into the phylogenetic taxonomy of Prototheca spp. in relationship to the CYP51/ERG11 structure and development of novel therapeutic drugs for the treatment of protothecosis.Lay SummaryCases of infection by microalgae of Prototheca species are increasing. However, effective treatment has not been established yet. In this study, gene and structure of Prototheca’s CYP51/ERG11, an enzyme which might serve as a target for therapeutic drugs, were characterized for the first time.