Over the last several decades, nearly 80% of anticancer drugs have been discovered from natural sources (e.g. bacteria, fungi, plants) or are derivatives of these natural products. Until the mid 2000s, the prevailing paradigm in natural product discovery centered on bioactivity-guided fractionation; however the genomics revolution greatly changed the field. As microbial genome sequencing has become more widespread, the capacity of microorganisms to produce natural products has come into better view. We have probed and surveyed this capacity using computational and expression screening to target a specific sub-class of natural products: those emerging from biosynthetic pathways with terminal reductase domains. Based upon the biological activity of compounds known to be produced by reductase terminating pathways, we have determined that natural products of this sub-class have a higher likelihood of exhibiting a clinically valuable activity when compared against all natural products. By surveying 344 actinobacterial genomes, we have identified 139 biosynthetic gene clusters in 12 families that terminate with an NAD(P)H-dependent reductase domain and performed expression screening of these clusters using mass spectrometry-based proteomics and metabolomics. This omics-based approach to genome mining has led to the targeted detection and structure elucidation of a new class of nonribosomal peptide and polyketide hybrids, the rimosamides A-D. The rimosamides are biosynthesized through a mixed NRPS/PKS pathway terminating with an unusual use of non‑canonical PKS building blocks (in both iterative and non-iterative fashion) along with a reductive release, which leads to the installation of the hemi‑aminal common to both 14 and 16 member ring rimosamides. This triple-omics study serves as an early example for how big data from the microbial world can be efficiently sifted through for high-value targets in specific compound classes.

Omics-based discovery of the rimosamides: A new class of nonribosomal peptide-polyketide hybrids

249th National Meeting (2015)

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