Epigenetic modulation of Ceratorhiza hydrophila by 5-azacytidine enhances antifungal metabolite production: insights from antimicrobial, metabolic, genomic and computational analyses.

IF 4.2 2区 生物学 Q2 MICROBIOLOGY
Rehab M Abdelhamid, Elham R S Soliman, Eslam T Mohamed, Yasmin M Elsaba
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引用次数: 0

Abstract

Background: The emergence of drug-resistant pathogens has stimulated the need for the development of new antimicrobial agents. Epigenetic modulation by suppressing epigenetic inhibitors, such as 5-azacytidine (5-aza), has been shown to activate silent biosynthetic gene clusters within a fungus and causes the production of novel secondary metabolites. This research examined this epigenetic modification strategy in the poorly studied filamentous fungus, Ceratorhiza hydrophila, which may help induce the additional production of bioactive compounds.

Results: The results from genomic and spectroscopic analyses (ISSR profiling and FTIR spectroscopy) indicated that 50 µM 5-aza produced substantial global DNA demethylation and genomic changes in C. hydrophila with no impact on cell viability. The epigenetic changes associated with the DNA demethylation prompted a notable and selective change in antimicrobial profile to suppress antibacterial activity against strains such as Clostridium sporogenes while also showing a robust induction of antifungal activity against Candida albicans (22 mm inhibition zone). GC-MS was performed for a deep-dive characterization of the metabolic profile which revealed, for example, a dramatic alteration of the profile including production of new secondary metabolites such as a novel indole derivative and diisooctyl phthalate, which did not exist in the untreated control. In silico analyses, such as modelling the promoter and molecular docking opportunities, offered a believable mechanistic rationale for the effects seen, linked to the predicted modulation of primary biosynthetic pathways.

Conclusion: This study demonstrates that epigenetic modulation can be used to successfully unlock latent biosynthetic capability in C. hydrophila resulting in the production of unique compounds with strong and selective antifungal activity. These results demonstrate the advantages of epigenetic screening of unique fungal sources in the search for new drug leads.

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5-氮扎胞苷对亲水角蜂的表观遗传调控增强了抗真菌代谢物的产生:来自抗菌、代谢、基因组和计算分析的见解。
背景:耐药病原体的出现刺激了开发新型抗菌药物的需求。通过抑制表观遗传抑制剂的表观遗传调节,如5-氮杂胞苷(5-aza),已被证明可以激活真菌内沉默的生物合成基因簇,并导致新的次级代谢物的产生。本研究在研究较少的丝状真菌——嗜水角菌中检测了这种表观遗传修饰策略,这可能有助于诱导额外的生物活性化合物的产生。结果:基因组和光谱分析(ISSR分析和FTIR光谱)结果表明,50µM 5-aza在嗜水菌中产生了大量的DNA去甲基化和基因组变化,但对细胞活力没有影响。与DNA去甲基化相关的表观遗传变化引起了抗菌谱的显著和选择性变化,以抑制对芽孢梭菌等菌株的抗菌活性,同时也显示出对白色念珠菌的抗真菌活性(22 mm抑制区)。采用气相色谱-质谱对代谢谱进行了深入的表征,结果显示,例如,代谢谱发生了巨大的变化,包括产生了新的次级代谢物,如一种新的吲哚衍生物和邻苯二甲酸二异辛酯,而这些在未经处理的对照组中不存在。计算机分析,如模拟启动子和分子对接机会,为所看到的效应提供了可信的机制基础,与预测的主要生物合成途径的调节有关。结论:本研究表明,表观遗传调控可以成功地开启嗜水酵母潜在的生物合成能力,从而产生具有强选择性抗真菌活性的独特化合物。这些结果证明了独特真菌来源的表观遗传筛选在寻找新药线索中的优势。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
BMC Microbiology
BMC Microbiology 生物-微生物学
CiteScore
7.20
自引率
0.00%
发文量
280
审稿时长
3 months
期刊介绍: BMC Microbiology is an open access, peer-reviewed journal that considers articles on analytical and functional studies of prokaryotic and eukaryotic microorganisms, viruses and small parasites, as well as host and therapeutic responses to them and their interaction with the environment.
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