Unearthing fungal chemodiversity

我们这个时代对全球健康和粮食安全的最大威胁之一是抗生素耐药性（AMR），导致现有的抗生素对人类和牲畜的治疗无效。为了应对AMR危机，需要发现新的抗生素，而大部分抗生素作为天然产物来源于真菌、细菌和植物。这些物质也称为次级代谢物，是生物体产生的，因为它们提供了生态和物理优势，以便更好地在其栖息地生存。丝状真菌是农业化学、食品和制药工业使用的生物活性化合物的长期来源。对真菌基因组的生物信息学分析表明，真菌含有大量的基因簇，这些基因簇似乎编码次级代谢产物的途径，但它们的化学产物是未知的，使得它们无法用于药物发现研究。提高我们的理解，这个基因簇是如何调节和功能分析，使用异源表达系统可能会导致发现新的天然产物，这些可能包括新类别的antibiotics.Project planThe首要目的，这项研究是调查新的生物活性分子和生物合成基因簇，调节它们的生产在几种不同的真菌。在这个多学科的项目中，微生物学，生物信息学和化学技术将用于发现新的天然产物，并研究其生物和生态活性。该项目有三个主要目标。目的1.优化异源宿主A.在一些独特的BGC的表达中鉴定了CINSAR 1。A. JNSAR 1已经被广泛用作异源表达菌株。将使用一系列分析技术对任何新的代谢产物进行表征，并筛选其生物活性。目标2.对两种新分离的真菌进行生物信息学和代谢组学分析，将有助于鉴定其生物活性代谢产物。化学分析将描述新化合物的结构。目标3.开发内源性转化和功能分析将研究新化合物与其BGC之间的联系。该方法将用于研究这些化合物的生物合成，并将用于产生新的衍生物用于生物活性研究。在项目期间将采用的技术：1。微生物发酵2.基因操作3.通过制备型HPLC纯化天然产物4. LC-MS/MS用于代谢物分析和去复制5。用MS和NMR技术进行结构解析6.抗微生物活性测定，包括MIC测定7。生物信息

One of the biggest threats to global health and food security of our time is antibiotic resistance (AMR) causing existing antibiotics to become ineffective as a treatment for humans and livestock. In order to tackle the AMR crisis, new antibiotics need to be discovered and a large proportion of antibiotics originate from fungi, bacteria and plants as natural products. These, also called secondary metabolites, are produced by organisms as they provide an ecological and physical advantage to better survive in their habitat. Filamentous fungi are a long-time source of bioactive compounds used by agrochemical, food, and pharmaceutical industries. Bioinformatic analyses of fungal genomes have revealed that fungi contain a large number of gene clusters which appear to encode pathways for secondary metabolites, yet their chemical products are unknown making them inaccessible for drug discovery studies. Improvement in our understanding of how this gene clusters are regulated and functional analysis using heterologous expression systems could lead to the discovery of new natural products, and these may include new classes of antibiotic.Project planThe overarching aim of this study is to investigate novel bioactive molecules and the biosynthetic gene clusters that regulate their production in several different fungi. In this multidisciplinary project, microbiological, bioinformatic and chemical techniques will be used to discover new natural products and investigate their biological and ecological activities. The project has three main objectives. OBJECTIVE 1. Optimize the heterologous host A. oryzae NSAR1 for the expression of several unique BGCs identified. A. oryzae NSAR1 is already used widely as a heterologous expression strain. Any new metabolite will be characterized using a range of analytical techniques and screened for bioactivities. OBJECTIVE 2. Bioinformatics and metabolomics analysis of two newly isolated fungal species will enable the identification of bioactive metabolites. Chemical analysis will characterize the structure of new compounds. OBJECTIVE 3. Development endogenous transformation and functional analysis will investigate the link between the new compounds to their BGCs. This method will be used to investigate the biosynthesis of these compounds and will be used to generate new derivatives for bioactivity studies. Techniques that will be undertaken during the project:1. Microorganism fermentation2. Genetic manipulation3. Natural product purification through preparative HPLC4. LC-MS/MS for metabolite profiling and dereplication5. Structural elucidation with MS and NMR techniques6. Antimicrobial activity assays, including MIC determination7. Bioinformatics