Accessing Bioactive Natural Products from the Human Microbiome

Abstract

Natural products have long played a pivotal role in the development of therapeutics for a variety of diseases. Traditionally, soil and marine environments have provided a rich reservoir from which diverse chemical scaffolds could be discovered. Recently, the human microbiome has been recognized as a promising niche from which secondary metabolites with therapeutic potential have begun to be isolated. In this Review, we address how the expansive history of identifying bacterial natural products in other environments is informing the approaches being brought to bear on the study of the human microbiota. We also touch on how these tools can lead to insights about microbe-microbe and host-microbe interactions and help generate biological hypotheses that may lead to developments of new therapeutic modalities.

Figure 1.. Functional Metagenomics Workflow

(A) Schematic outline of the functional (meta)genomics mining approach used in the discovery of commendamide, a GPCR agonist. (B) Functional (meta)genomics provides direct access to the biosynthetic gene(s) responsible for metabolite production, which can then be used to mine available sequence data for similar biosynthetic pathways. This can lead to the discovery of chemically similar metabolites with related function, as was the case with the commendamide-inspired discovery of a second N-acyl GPCR agonist, N-acyl serinol.

Figure 2.. Sequence-Based (Meta)genomics Workflows

(A) Sequence-based (meta)genomics leverages the power of predictive bioinformatics tools to identify biosynthetic gene clusters in the available sequence data and guide the targeted discovery of bacterial metabolites. This approach was used to discover the novel antibiotic lactocillin and various dipeptide aldehydes with implications in mammalian protease inhibition. (B) In the synthetic-bioinformatic natural product (syn-BNP) workflow, specific chemical structures of natural products are predicted from analyses of biosynthetic gene clusters, and these molecules are chemically synthesized and subsequently tested for biological activity, such as antibiosis in the case of the humimycins.

Figure 3.. Simple Aromatic Amino Acids with Demonstrated Effects in Microbe-Host Relationship

A growing number of simple derivatives of aromatic amino acids (inside the box) have been found to not only be produced by commensal bacteria but elicit functional responses during in vitro or in vivo biological experiments. These studies suggest that bacteria take advantage of simple enzymatic processes using abundant substrates to interact with their environment. Color of derivatives indicates matching amino acid source.

Figure 4.. Chemistry-Forward Discovery Workflow

Traditional, chemistry-forward approaches do not rely on biosynthetic gene sequence information but instead use analytical techniques (e.g., pyroglutamate containing compounds) or functional assays (e.g., lugdunin) to identify metabolites of interest from bacterial strains after laboratory cultivation.