Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases

Chun Jun Guo, Fang Yuan Chang, Thomas P. Wyche, Keriann M. Backus, Timothy M. Acker, Masanori Funabashi, Mao Taketani, Mohamed S. Abou Donia, Stephen Nayfach, Katherine S. Pollard, Charles S. Craik, Benjamin F. Cravatt, Jon Clardy, Christopher A. Voigt, Michael A. Fischbach

Research output: Contribution to journalArticlepeer-review

160 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)517-526.e18
Issue number3
StatePublished - Jan 26 2017

All Science Journal Classification (ASJC) codes

  • General Biochemistry, Genetics and Molecular Biology


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


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