Cellular stress upregulates indole signaling metabolites in E. coli

Escherichia coli broadly colonize the intestinal tracts of humans and produce a variety of small molecule signals to regulate group bacterial behaviors and host responses. However, many of these small molecules remain unknown. Here, we describe a family of bacterial metabolites (1-5) termed the “indolokines,” which were identified in mouse fecal samples. In E. coli, the indolokines are upregulated in response to a redox stressor via aspC- and tyrB-mediated aromatic amino acid transamination. While indolokine 1 represents a previously unreported small molecule, four of the indolokines (2-5) were previously shown to be derived from indole-3-carbonyl nitrile (ICN), a molecule associated with the plant pathogen defense response. We show that the bacterial molecules are produced in a convergent evolutionary manner relative to plants and enhance E. coli persister cell formation, an antibiotic tolerant state. Additionally, we demonstrate that select indolokines outperform ICN protection in an Arabadopsis thaliana-Pseudomonas syringae infection model by several orders of magnitude, suggesting that the indolokines are defense signaling molecules in both bacteria and plants. We also test the indolokines in primary human tissues and observe diverse immunological responses, including robust regulation of interleukin-6 (IL-6). The indolokines potently signal via the human aryl-hydrocarbon receptor (AhR), which likely accounts for the IL-6 phenotype. Our molecular studies link a family of cellular stress-induced metabolites to defensive responses across bacteria, plants, and humans.