| Summary: | Microorganisms are Nature's little engineers of a remarkable array of bioactive small molecules that represent most of our new drugs. The wealth of genomic and metagenomic sequence data generated in the last decade has shown that the majority of novel biosynthetic gene clusters (BGCs) is identified from cultivation-independent studies, which has led to a strong expansion of the number of microbial taxa known to harbour BGCs. The large size and repeat sequences of BGCs remain a bioinformatic challenge, but newly developed software tools have been created to overcome these issues and are paramount to identify and select the most promising BGCs for further research and exploitation. Although heterologous expression of BGCs has been the greatest challenge until now, a growing number of polyketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS)-encoding gene clusters have been cloned and expressed in bacteria and fungi based on techniques that mostly rely on homologous recombination. Finally, combining ecological insights with state-of-the-art computation and molecular methodologies will allow for further comprehension and exploitation of microbial specialized metabolites. Highlights • Environments that are most promising sources of new bioactives were identified. • New computational sequence binning tools improve large gene cluster reconstruction. • New cloning tools have led to the first successful heterologous expression of BGCs. CL was funded by NWO-VLAG grant Mare incognita, MHM was supported by VENI grant 863.15.002 from The Netherlands Organization for Scientific Research (NWO), JvdO is supported by the Netherlands Organization for Scientific Research (NWO) by a TOP grant (714.015.001) and DS acknowledges funding from the European Union's Horizon 2020 research and innovation program under Grant Agreement No. 679849 (SponGES).
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