biostudies-literatureGatsios ANCATS NIH HHSHoward Hughes Medical InstituteNational Institute of General Medical SciencesNIGMS NIH HHS2626-2640https://www.ebi.ac.uk/biostudies/studies/S-EPMC9949963biostudies-literatureUnknown85(11)<i>Escherichia coli</i> isolates commonly inhabit the human microbiota, yet the majority of <i>E. coli</i>'s small-molecule repertoire remains uncharacterized. We previously employed erythromycin-induced translational stress to facilitate the characterization of autoinducer-3 (AI-3) and structurally related pyrazinones derived from "abortive" tRNA synthetase reactions in pathogenic, commensal, and probiotic <i>E. coli</i> isolates. In this study, we explored the "missing" tryptophan-derived pyrazinone reaction and characterized two other families of metabolites that were similarly upregulated under erythromycin stress. Strikingly, the abortive tryptophanyl-tRNA synthetase reaction leads to a tetracyclic indole alkaloid metabolite (<b>1</b>) rather than a pyrazinone. Furthermore, erythromycJournal of natural productsCellular Stress-Induced Metabolites in <i>Escherichia coli</i>.PMC99499631RM1GM141649-01UL1 TR001863RM1 GM141649Crawford JMKim CSFlavell RAYork AGGatsios AfalseCellular Stress-Induced Metabolites in <i>Escherichia coli</i>.<i>Escherichia coli</i> isolates commonly inhabit the human microbiota, yet the majority of <i>E. coli</i>'s small-molecule repertoire remains uncharacterized. We previously employed erythromycin-induced translational stress to facilitate the characterization of autoinducer-3 (AI-3) and structurally related pyrazinones derived from "abortive" tRNA synthetase reactions in pathogenic, commensal, and probiotic <i>E. coli</i> isolates. In this study, we explored the "missing" tryptophan-derived pyrazinone reaction and characterized two other families of metabolites that were similarly upregulated under erythromycin stress. Strikingly, the abortive tryptophanyl-tRNA synthetase reaction leads to a tetracyclic indole alkaloid metabolite (<b>1</b>) rather than a pyrazinone. Furthermore, erythromyc2022-01-01T00:00:00Z2022 Nov2026-06-06T21:12:14.611Z2025-04-04T14:29:51.292ZS-EPMC99499633634662510.1021/acs.jnatprod.2c00706