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Sulfamethoxazole drug stress upregulates antioxidant immunomodulatory metabolites in Escherichia coli.
Park, Hyun Bong; Wei, Zheng; Oh, Joonseok; Xu, Hao; Kim, Chung Sub; Wang, Rurun; Wyche, Thomas P; Piizzi, Grazia; Flavell, Richard A; Crawford, Jason M.
Afiliação
  • Park HB; Department of Chemistry, Yale University, New Haven, CT, USA.
  • Wei Z; Chemical Biology Institute, Yale University, West Haven, CT, USA.
  • Oh J; Chemical Biology Institute, Yale University, West Haven, CT, USA.
  • Xu H; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
  • Kim CS; Department of Chemistry, Yale University, New Haven, CT, USA.
  • Wang R; Chemical Biology Institute, Yale University, West Haven, CT, USA.
  • Wyche TP; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
  • Piizzi G; Department of Chemistry, Yale University, New Haven, CT, USA.
  • Flavell RA; Chemical Biology Institute, Yale University, West Haven, CT, USA.
  • Crawford JM; School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
Nat Microbiol ; 5(11): 1319-1329, 2020 11.
Article em En | MEDLINE | ID: mdl-32719505
ABSTRACT
Escherichia coli is an important model organism in microbiology and a prominent member of the human microbiota1. Environmental isolates readily colonize the gastrointestinal tract of humans and other animals, and they can serve diverse probiotic, commensal and pathogenic roles in the host2-4. 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 IBD6,7. The genes folX/M and aspC/tyrB involved in monapterin biosynthesis8-10 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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pteridinas / Sulfametoxazol / Escherichia coli / Imunomodulação / Antioxidantes Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pteridinas / Sulfametoxazol / Escherichia coli / Imunomodulação / Antioxidantes Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article