Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases

Publication date: Available online 19 January 2017
Source:Cell
Author(s): Chun-Jun Guo, Fang-Yuan Chang, Thomas P. Wyche, Keriann M. Backus, Timothy M. Acker, Masanori Funabashi, Mao Taketani, Mohamed S. Donia, Stephen Nayfach, Katherine S. Pollard, Charles S. Craik, Benjamin F. Cravatt, Jon Clardy, Christopher A. Voigt, Michael A. Fischbach
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.

Graphical abstract

Teaser

Guo et al. report the discovery of a new family of microbial metabolites that are widely produced by the microbes of the human gut and that chemically modify host cellular proteins.


from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2jTQhKT
via IFTTT