NATURAL PRODUCTS DISCOVERY AND BIOENGINEERING NETWORK (NPRONET)

许多微生物和植物产生的分子具有广泛的生物活性。这些天然产物，也被称为次生代谢物，已被用于许多重磅药物的开发，包括抗癌、免疫抑制剂和降胆固醇剂。此外，临床使用的大多数抗生素都来自天然产物。尽管如此，近年来以天然产物为基础的新药的开发已经下降。特别是新抗生素的供应已经减少，以至于抗生素耐药病原体（超级细菌）现在被广泛认为是一个主要的全球健康威胁。天然产物在农业中也被用作除草剂、杀虫剂和杀菌剂，以提高作物产量，从而帮助养活不断增长的人口。此外，天然产品还用于其他商业产品，包括香水和调味品。基因序列技术的最新进展使许多产生次生代谢物的微生物和植物的全基因组序列得以确定。这揭示了许多新的基因簇，它们编码组装天然产物所需的必要酶。然而，在正常的实验室条件下，这些基因簇中的许多要么是沉默的，要么不会产生可检测数量的化合物。因此，自然界有可能产生比以前想象的更多的次生代谢物。NPRONET的中心目标将是设计激活这些沉默或低产量基因簇的方法。例如，非生产性基因簇可以在经过基因改造以提高次生代谢物产量的替代宿主菌株中转移和表达。这将需要新的计算和实验技术的发展，这些技术可以用于快速设计宿主菌株和操纵大型基因簇。在某些情况下，需要设计新的调控元件来控制基因簇的表达。最终，这将使新的次级代谢物能够大量生产，足以用于商业开发。许多天然产物是高度复杂的分子，很难用传统化学方法合成或修饰。因此，通常很难产生具有增强生物活性或改进物理性质的结构变体或第二代分子，以用于随后的商业应用。因此，NPRONET将开发新的生物工程方法和工具，这将使最有希望的天然产物分子的结构快速多样化和优化。为此，NPRONET将建立对一些最有希望的天然产物组装机制的详细了解。然后，这些知识将用于重新编程特定的基因集群，以使替代前体的结合，组装的重新排序或引入不同的剪裁修饰（甲基化，糖基化，羟化酶，卤化等）。为了解决这些重大的工业和社会挑战，NPRONET将需要多学科，汇集化学家，生物学家，计算科学家，对天然产物发现和生物工程感兴趣的工程师和其他人员。这将包括来自学术界和工业界（小型和大型）以及其他终端用户群体的研究领导人。通过一系列网络活动、概念验证资助和其他活动，NPRONET将促进新的合作伙伴关系，探索新的合作方式，从而加速天然产品的发现和生物工程进程。

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.