Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases.

TitleDiscovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases.
Publication TypeJournal Article
Year of Publication2017
AuthorsGuo, C-J, Chang, F-Y, Wyche, TP, Backus, KM, Acker, TM, Funabashi, M, Taketani, M, Donia, MS, Nayfach, S, Pollard, KS, Craik, CS, Cravatt, BF, Clardy, J, Voigt, CA, Fischbach, MA
JournalCell
Volume168
Issue3
Pagination517-526.e18
Date Published2017 01 26
ISSN1097-4172
KeywordsAnimals, Bacillus subtilis, Bacteria, Escherichia coli, Feces, Gastrointestinal Microbiome, Humans, Microbiota, Peptide Synthases, Phylogeny, Pyrazines
Abstract

<p>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.</p>

DOI10.1016/j.cell.2016.12.021
Alternate JournalCell
PubMed ID28111075
PubMed Central IDPMC5302092
Grant ListR01 GM104659 / GM / NIGMS NIH HHS / United States
R37 CA087660 / CA / NCI NIH HHS / United States
R01 DK101674 / DK / NIDDK NIH HHS / United States
R01 AT009874 / AT / NCCIH NIH HHS / United States
T32 GM067547 / GM / NIGMS NIH HHS / United States
F32 GM111012 / GM / NIGMS NIH HHS / United States
R01 DK110174 / DK / NIDDK NIH HHS / United States