@article{8ab5263bdc6e4e3fbf5c025de72ccc9c,
title = "Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases",
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",
author = "Guo, {Chun Jun} and Chang, {Fang Yuan} and Wyche, {Thomas P.} and Backus, {Keriann M.} and Acker, {Timothy M.} and Masanori Funabashi and Mao Taketani and {Abou Donia}, {Mohamed S.} and Stephen Nayfach and Pollard, {Katherine S.} and Craik, {Charles S.} and Cravatt, {Benjamin F.} and Jon Clardy and Voigt, {Christopher A.} and Fischbach, {Michael A.}",
note = "Funding Information: We are deeply grateful to Piro Siuti and Horst Hemmerle at Novartis for their many constructive discussions and support of this research program, Emma Allen-Vercoe for sending us Lachnospiraceae sp. 3_1_57FAA and Ruminococcus sp. 5_1_39BFAA, Kim Lewis and Phil Strandwitz for providing us with Clostridium sp. KLE 1755, Jeff Johnson and Nevan Krogan for help with MS/MS experiments, Hiroki Shimizu and Adam Renslo for help with the chemical synthesis of peptide aldehydes, three anonymous reviewers for constructive suggestions, and members of the Fischbach Group for helpful comments. This work was supported by the BASF California Research Alliance (M.A.F.) grants from the NIH (R01 DK101674, R01 DK110174, and DP1 DK113598 [M.A.F.], R01 CA087660 [B.F.C.], DP2 AI124441 [M.S.D.], and R01 GM104659 [C.S.C.]), a fellowship from the David and Lucile Packard Foundation (M.A.F.), an HHMI-Simons Faculty Scholars Award (M.A.F.), a research award from Novartis (M.A.F., C.A.V., and J.C.); research awards from the U.S. Defense Advanced Research Projects Agency's Living Foundries program (HR0011-12-C-0067, HR0011-13-1-001, and HR0011-15-C-0084 [C.A.V. and M.A.F.]), a Ruth L. Kirschstein National Research Service Award (NRSA) Individual Postdoctoral Fellowship (5F32GM111012-03 [T.M.A.]), and a Burroughs Welcome Fund Investigators in the Pathogenesis of Infectious Disease award (M.A.F.). M.A.F. is a member of the board of directors of Achaogen and the scientific advisory boards of NGM Biopharmaceuticals and Cell Design Labs and is a co-founder of Revolution Medicines. C.A.V. is a co-founder and scientific advisory board member of Pivot Bio, and on the scientific advisory boards of DSM, Twist Bio, SynLogic, Biomilenia, Senti Bio, Bolt Threads, and Zymergen. K.S.P. is a consultant for Phylagen Biosciences. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = jan,
day = "26",
doi = "10.1016/j.cell.2016.12.021",
language = "English (US)",
volume = "168",
pages = "517--526.e18",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",
}