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 tracts of humans and other animals, and they can serve diverse probiotic, commensal, and pathogenic roles in the host(2–4). Certain strains have been associated with the severity of inflammatory bowel disease (IBD)(2,5); however, 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 sub-inhibitory levels of the antifolate sulfamethoxazole (SMX), which is used to treat infections, including in IBD patients(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, harbor diverse immunological activities in primary human tissues, activate anti-inflammatory interleukin-10 (IL-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.