Sulfamethoxazole drug stress upregulates antioxidant immunomodulatory metabolites in Escherichia coli
Escherichia coli is an important model organism in microbiology and a prominent member of the human microbiota 1 . Environmental isolates readily colonize the gastrointestinal tract of humans and other animals, and they can serve diverse probiotic, commensal and pathogenic roles in the host 2 – 4 ....
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Published in | Nature microbiology Vol. 5; no. 11; pp. 1319 - 1329 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
01.11.2020
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | Escherichia coli
is an important model organism in microbiology and a prominent member of the human microbiota
1
. Environmental isolates readily colonize the gastrointestinal tract of humans and other animals, and they can serve diverse probiotic, commensal and pathogenic roles in the host
2
–
4
. Although certain strains have been associated with the severity of inflammatory bowel disease (IBD)
2
,
5
, the diverse immunomodulatory phenotypes remain largely unknown at the molecular level. Here, we decode a previously unknown
E. coli
metabolic pathway that produces a family of hybrid pterin–phenylpyruvate conjugates, which we named the colipterins. The metabolites are upregulated by subinhibitory levels of the antifolate sulfamethoxazole, which is used to treat infections including in patients with IBD
6
,
7
. The genes
folX/M
and
aspC/tyrB
involved in monapterin biosynthesis
8
–
10
and aromatic amino acid transamination,
11
respectively, were required to initiate the colipterin pathway. We show that the colipterins are antioxidants, harbour diverse immunological activities in primary human tissues, activate anti-inflammatory interleukin-10 and improve colitis symptoms in a colitis mouse model. Our study defines an antifolate stress response in
E. coli
and links its associated metabolites to a major immunological marker of IBD.
Subinhibitory levels of sulfamethoxazole, an antibiotic used to treat
Escherichia coli
infections, trigger a previously undescribed metabolic pathway in
E. coli
that comprises a family of hybrid pterin–phenylpyruvate conjugates called colipterins. These metabolites are antioxidants, have immunomodulatory properties and improve colitis in a murine model. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 H.B.P. and J.M.C. conceived the study and designed the metabolism experiments. H.B.P. characterized the colipterin pathway from E. coli via drug stress, metabolome analysis, isolation, structure characterization, synthesis, genetic complementation, and antioxidant assays. Z.W. performed ELISA assays for IL-8/IL-10 and all mouse studies. J.O. performed CP-3 computational analysis on colipterins 1/2 and contributed to colipterin accumulation and NMR measurements. H.X. maintained the IL-10eGFP mice, isolated immune cells from the small intestine, and analyzed FACS data for the IL-10 expression. C.S.K. constructed double mutant strains of aspC and tyrB. R.W., T.P.W, and G.P. contributed to BioMap® analysis of the colipterins. R.A.F conceived and supervised the in vivo mouse studies. H.B.P. and J.M.C. wrote the manuscript with input from all of the authors. All authors reviewed and edited the manuscript. Author contributions |
ISSN: | 2058-5276 2058-5276 |
DOI: | 10.1038/s41564-020-0763-4 |