Sequence-guided mining of metagenomic libraries provides a means of recovering specific natural product gene clusters of interest from the environment. In this study, we use ketosynthase gene (KS) PCR amplicon sequences (sequence tags) to explore the structural and biosynthetic diversities of pentangular polyphenols (PP). In phylogenetic analyses, eDNA-derived sequence tags often fall between closely related clades that are associated with gene clusters known to encode distinct chemotypes. We show that these common “intermediate” sequence tags are useful for guiding the discovery of not only novel bioactive metabolites but also collections of closely related gene clusters that can provide new insights into the evolution of natural product structural diversity. Gene clusters corresponding to two eDNA-derived KS β sequence tags that reside between well-defined KS β clades associated with the biosynthesis of (C24)-pradimicin and (C26)-xantholipin type metabolites were recovered from archived soil eDNA libraries. Heterologous expression of these gene clusters in Streptomyces albus led to the isolation of three new PPs (compounds 1– 3).

Calixanthomycin A ( 1) shows potent antiproliferative activity against HCT-116 cells, whereas arenimycins C ( 2) and D ( 3) display potent antibacterial activity. By comparing genotypes and chemotypes across all known PP gene clusters, we define four PP subfamilies, and also observe that the horizontal transfer of PP tailoring genes has likely been restricted to gene clusters that encode closely related chemical structures, suggesting that only a fraction of the “natural product-like” chemical space that can theoretically be encoded by these secondary metabolite tailoring genes has likely been sampled naturally. The analysis of DNA sequence is increasingly being used to guide the discovery of natural product biosynthetic gene clusters capable of encoding for novel metabolites. When studying cultured bacteria, it is possible to fully sequence a bacterial genome and therefore carry out detailed analyses of complete biosynthetic gene clusters to identify those likely to encode for novel metabolites.

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Similar full gene cluster analyses are not usually possible when exploring complex environmental microbiomes because the immense size of most metagenomes precludes full sequencing and assembly of complete gene clusters. To circumvent this limitation, we and others have explored the use of the detailed phylogenetic analysis of individual, highly conserved natural product biosynthetic genes as markers for guiding the discovery of functionally novel natural product biosynthetic gene clusters from complex metagenomes.

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