Unearthing fungal chemodiversity

点击翻译按钮获取中文摘要

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