Cell
Volume 168, Issue 3, 26 January 2017, Pages 517-526.e18
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Article
Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases

https://doi.org/10.1016/j.cell.2016.12.021Get rights and content
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Highlights

  • A family of gene clusters in gut bacteria encodes dipeptide aldehydes

  • Present in 88% of humans and transcribed under conditions of host colonization

  • One compound, Phe-Phe-H, targets cathepsins in an unbiased cell-based assay

  • Uncovers a possible role for lysosomal proteases in microbiota-host interactions

Summary

The gut microbiota modulate host biology in numerous ways, but little is known about the molecular mediators of these interactions. Previously, we found a widely distributed family of nonribosomal peptide synthetase gene clusters in gut bacteria. Here, by expressing a subset of these clusters in Escherichia coli or Bacillus subtilis, we show that they encode pyrazinones and dihydropyrazinones. At least one of the 47 clusters is present in 88% of the National Institutes of Health Human Microbiome Project (NIH HMP) stool samples, and they are transcribed under conditions of host colonization. We present evidence that the active form of these molecules is the initially released peptide aldehyde, which bears potent protease inhibitory activity and selectively targets a subset of cathepsins in human cell proteomes. Our findings show that an approach combining bioinformatics, synthetic biology, and heterologous gene cluster expression can rapidly expand our knowledge of the metabolic potential of the microbiota while avoiding the challenges of cultivating fastidious commensals.

Keywords

microbiome
natural products
synthetic biology
metagenomics
biosynthetic gene cluster
peptide aldehyde
protease inhibitor

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