title: Steps towards the synthetic biology of polyketide biosynthesis.
abstract: 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.
authors.affiliation: Faculty of Life Sciences, Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Cummings
authors.forename: Rainer
authors.initials: R
authors.lastname: Breitling
authors.forename: Eriko
authors.initials: E
authors.lastname: Takano
mesh_terms: D000900:Anti-Bacterial Agents / Q000302:isolation & purification* / Q000378:metabolism*; D053898:Biosynthetic Pathways; D060847:Metabolic Engineering / Q000379:methods*; D061065:Polyketides / Q000302:isolation & purification* / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D061065:Polyketides
keywords: combinatorial biosynthesis; drug discovery; plug-and-play biology; refactoring; secondary metabolites