Metagenomic sequencing-driven multidisciplinary approaches to shed light on the untapped microbial natural products.

• Metagenomics can tap the untapped biosynthetic potential of uncultivable microbes. • Metagenomic sequencing facilitates the discovery of microbial specialized metabolites. • We highlight the compounds discovered by metagenomics in recent five years. • We suggest approaches to realize the metagenomic sequencing-predicted chemistry. The advantage of metagenomics over the culture-based natural product (NP) discovery pipeline is the ability to access the biosynthetic potential of uncultivable microbes. Advances in DNA sequencing are revolutionizing conventional metagenomics approaches for microbial NP discovery. The genomes of (in)cultivable bugs can be resolved straightforwardly from environmental samples, enabling in situ prediction of biosynthetic gene clusters (BGCs). The predicted chemical diversities could be realized not only by heterologous expression of gene clusters originating from DNA synthesis or direct cloning, but also potentially by bioinformatic-directed organic synthesis or chemoenzymatic total synthesis. In this review, we suggest that metagenomic sequencing in tandem with multidisciplinary approaches will form a versatile platform to shed light on a plethora of microbial 'dark matter'. [ABSTRACT FROM AUTHOR]