2. Academic Validation
  3. Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases

Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases

  • Cell. 2017 Jan 26;168(3):517-526.e18. doi: 10.1016/j.cell.2016.12.021.
Chun-Jun Guo 1,  Fang-Yuan Chang 2,  Thomas P Wyche 3,  Keriann M Backus 4,  Timothy M Acker 5,  Masanori Funabashi 1,  Mao Taketani 1,  Mohamed S Donia 6,  Stephen Nayfach 7,  Katherine S Pollard 7,  Charles S Craik 5,  Benjamin F Cravatt 4,  Jon Clardy 3,  Christopher A Voigt 2,  Michael A Fischbach 8
Affiliations

Affiliations

  • 1 Department of Bioengineering and Therapeutic Sciences and California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 2 Department of Biological Engineering and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02115, USA.
  • 3 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 4 Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92307, USA.
  • 5 Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 6 Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
  • 7 Integrative Program in Quantitative Biology, Gladstone Institutes, and Division of Biostatistics, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 8 Department of Bioengineering and Therapeutic Sciences and California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: fischbach@fischbachgroup.org.
PMID: 28111075 DOI: 10.1016/j.cell.2016.12.021
Abstract

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

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

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