Advances in mining and expressing microbial biosynthetic gene clusters.

Natural products (NPs) especially the secondary metabolites originated from microbes exhibit great importance in biomedical, industrial and agricultural applications. However, mining biosynthetic gene clusters (BGCs) to produce novel NPs has been hindered owing that a large population of environmental microbes are unculturable. In the past decade, strategies to explore BGCs directly from (meta)genomes have been established along with the fast development of high-throughput sequencing technologies and the powerful bioinformatics data-processing tools, which greatly expedited the exploitations of novel BGCs from unculturable microbes including the extremophilic microbes. In this review, we firstly summarized the popular bioinformatics tools and databases available to mine novel BGCs from (meta)genomes based on either pure cultures or pristine environmental samples. Noticeably, approaches rooted from machine learning and deep learning with focuses on the prediction of ribosomally synthesized and post-translationally modified peptides (RiPPs) were dramatically increased in recent years. Moreover, synthetic biology techniques to express the novel BGCs in culturable native microbes or heterologous hosts were introduced. This working pipeline including the discovery and biosynthesis of novel NPs will greatly advance the exploitations of the abundant but unexplored microbial BGCs.