Triastuti Asih, Vansteelandt Marieke, Barakat Fatima, Trinel Manon, Jargeat Patricia, Fabre Nicolas, Amasifuen Guerra Carlos A, Mejia Kember, Valentin Alexis, Haddad Mohamed
UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, 31400, Toulouse, France.
Laboratory Pharmaceutical Biology, Department of Pharmacy, UII, Yogyakarta, 55584, Indonesia.
Chem Biodivers. 2019 Apr;16(4):e1800485. doi: 10.1002/cbdv.201800485. Epub 2019 Mar 20.
Fungi are talented organisms able to produce several natural products with a wide range of structural and pharmacological activities. The conventional fungal cultivation used in laboratories is too poor to mimic the natural habitats of fungi, and this can partially explain why most of the genes responsible for the production of metabolites are transcriptionally silenced. The use of Histone Deacetylase inhibitors (HDACis) to perturb fungal secondary biosynthetic machinery has proven to be an effective approach for discovering new fungal natural products. The present study relates the effects of suberoylanilide hydroxamic acid (SAHA) and sodium valproate (VS) on the metabolome of Botryosphaeria mamane, an endophytic fungus isolated from Bixa orellana L. UHPLC/HR-MS analysis, integrated with four metabolomics tools: MS-DIAL, MS-FINDER, MetaboAnalyst and GNPS molecular networking, was established. This study highlighted that SAHA and VS changed metabolites in B. mamane, causing upregulation and downregulation of metabolites production. In addition, twelve compounds were detected in the extracts as metabolites structurally correlated to SAHA, indicating its important reactivity in the medium or its metabolism by the fungus. An addition of SAHA induced the production of eight metabolites while VS induced only two metabolites undetected in the control strain. This result illustrates the importance of adding HDACis to a fungal culture in order to induce metabolite production.
真菌是有能力产生多种具有广泛结构和药理活性的天然产物的生物体。实验室中使用的传统真菌培养方法过于简陋，无法模拟真菌的自然栖息地，这可以部分解释为什么大多数负责代谢产物产生的基因在转录上是沉默的。使用组蛋白脱乙酰酶抑制剂（HDACis）来干扰真菌的次生生物合成机制已被证明是发现新的真菌天然产物的有效方法。本研究探讨了辛二酰苯胺异羟肟酸（SAHA）和丙戊酸钠（VS）对从红木（Bixa orellana L.）中分离出的内生真菌马马内葡萄座腔菌（Botryosphaeria mamane）代谢组的影响。建立了超高效液相色谱/高分辨质谱（UHPLC/HR-MS）分析方法，并结合了四种代谢组学工具：MS-DIAL、MS-FINDER、MetaboAnalyst和GNPS分子网络。该研究强调，SAHA和VS改变了马马内葡萄座腔菌中的代谢产物，导致代谢产物产生的上调和下调。此外，在提取物中检测到12种化合物作为与SAHA结构相关的代谢产物，表明其在培养基中的重要反应性或被真菌代谢的情况。添加SAHA诱导产生了8种代谢产物，而VS仅诱导产生了对照菌株中未检测到的2种代谢产物。这一结果说明了向真菌培养物中添加HDACis以诱导代谢产物产生的重要性。
