Faculty of Life Sciences, Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK.
FEMS Microbiol Lett. 2014 Feb;351(2):116-25. doi: 10.1111/1574-6968.12365. Epub 2014 Jan 7.
Nature is providing a bountiful pool of valuable secondary metabolites, many of which possess therapeutic properties. However, the discovery of new bioactive secondary metabolites is slowing down, at a time when the rise of multidrug-resistant pathogens and the realization of acute and long-term side effects of widely used drugs lead to an urgent need for new therapeutic agents. Approaches such as synthetic biology are promising to deliver a much-needed boost to secondary metabolite drug development through plug-and-play optimized hosts and refactoring novel or cryptic bacterial gene clusters. Here, we discuss this prospect focusing on one comprehensively studied class of clinically relevant bioactive molecules, the polyketides. Extensive efforts towards optimization and derivatization of compounds via combinatorial biosynthesis and classical engineering have elucidated the modularity, flexibility and promiscuity of polyketide biosynthetic enzymes. Hence, a synthetic biology approach can build upon a solid basis of guidelines and principles, while providing a new perspective towards the discovery and generation of novel and new-to-nature compounds. We discuss the lessons learned from the classical engineering of polyketide synthases and indicate their importance when attempting to engineer biosynthetic pathways using synthetic biology approaches for the introduction of novelty and overexpression of products in a controllable manner.
自然界提供了丰富的有价值的次生代谢产物，其中许多具有治疗特性。然而，新的生物活性次生代谢产物的发现速度正在放缓，而此时多药耐药病原体的兴起以及广泛使用的药物的急性和长期副作用的认识，导致人们迫切需要新的治疗药物。合成生物学等方法有望通过即插即用的优化宿主和重构新型或隐匿的细菌基因簇，为次生代谢物药物开发提供急需的推动力。在这里，我们重点讨论了经过全面研究的一类具有临床相关性的生物活性分子——聚酮化合物，讨论了这一前景。通过组合生物合成和经典工程对化合物进行优化和衍生的广泛努力，阐明了聚酮生物合成酶的模块化、灵活性和混杂性。因此，合成生物学方法可以在坚实的指导方针和原则基础上，为发现和生成新型和自然界中不存在的化合物提供新的视角。我们讨论了从聚酮合酶的经典工程中吸取的经验教训，并指出在尝试使用合成生物学方法进行生物合成途径工程以可控的方式引入新颖性和过表达产物时，这些经验教训的重要性。
