NATURAL PRODUCTS DISCOVERY AND BIOENGINEERING NETWORK (NPRONET)

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Many microorganisms and plants produce molecules that possess a broad spectrum of biological activities. These natural products, also known as secondary metabolites, have been used in the development of many blockbuster drugs including anticancer, immunosuppressive, and cholesterol-lowering agents. Furthermore the majority of antibiotics in clinical use are derived from natural products. Despite this the development of new natural product based pharmaceuticals has declined in recent years. In particular the supply of new antibiotics has diminished to the extent that antibiotic-resistant pathogens (superbugs) are now widely recognised as a major global health threat. Natural products are also used in agriculture as herbicides, pesticides, and fungicides to increase crop yields which can help feed the growing population. In addition natural products are used in other commercial products including perfumes and flavourings.Recent advances in gene sequence technologies have enabled the entire genome sequence of many secondary metabolite producing microorganisms and plants to be determined. This has revealed many new clusters of genes that encode the necessary enzymes required to assemble natural products. However many of these gene clusters are either silent or do not give rise to detectable quantities of compound under normal laboratory conditions. Consequently nature has the potential to produce many more secondary metabolites than was ever envisaged. A central goal of NPRONET will be to devise methods for activating these silent or low yielding gene clusters. For example the unproductive gene clusters can be transferred and expressed in an alternative host strain which has been genetically modified to enhance production of secondary metabolites. This will require the development of new computational and experimental technologies that can be deployed to rapidly engineer host strains and manipulate large gene clusters. In some cases new regulatory elements will need to be designed which can be used to control expression of gene clusters. Ultimately this will enable new secondary metabolites to be produced in quantities sufficient for commercial development.Many natural products are highly complex molecules that are difficult to synthesise or modify using traditional chemistry. Consequently it is often difficult to generate structural variants, or second generation molecules, with enhanced biological activity or improved physical properties for subsequent commercial applications. NPRONET will therefore develop new bioengineering methods and tools which will enable rapid structural diversification and optimisation of the most promising natural product molecules. To do this NPRONET will establish a detailed understanding of the mechanisms by which some of the most promising natural products are assembled. This knowledge will then be used to re-program a specific gene cluster to enable incorporation of alternative precursors, the re-ordering of the assembly or the introduction of different tailoring modifications (methylation, glycosylation, hydroxylases, halogenation etc.)To tackle these major industrial and societal grand challenges NPRONET will need to be multidisciplinary, bringing together chemists, biologists, computational scientists, engineers and others who have interests in natural products discovery and bioengineering. This will include research leaders from both academia and industry (small and large) as well as other end-user groups. Through a series of network events, proof-of-concept funding and other activities NPRONET will facilitate new collaborative partnerships to explore new ways of working together that will accelerate the natural product discovery and bioengineering process.