Discovery of a Human Metabolite That Mimics the Bacterial Quorum-Sensing Autoinducer AI-2

Bacteria use small molecules to orchestrate collective behaviors in a process called quorum sensing (QS), which relies on the production, release, and group-wide detection of extracellular signal molecules referred to as autoinducers. One QS autoinducer, termed AI-2, is broadly used for interspecies bacterial communication, including in the mammalian gut. AI-2 consists of a family of interconverting compounds and adducts originating from 4,5-dihydroxy-2,3-pentanedione. This complex speciation, coupled with the inherent instability of AI-2 congeners, have complicated isolation efforts. It has been known that mammalian epithelial cells produce an AI-2 mimic to which bacteria respond. However, the identity of the AI-2 mimic has remained elusive, presumably due to its instability, similar to that of known AI-2 compounds. Here, we developed a reactivity-based metabolomics approach to capture and identify a mammalian AI-2 mimic. Using a chemical strategy targeted at the α-diketone moiety of known AI-2s, we identify the unusual sugar l-xylosone, as well as the related metabolite l-xylulose, as AI-2 mimics. While l-xylulose is a common and naturally occurring sugar known in human metabolism, l-xylosone is a rare and highly reactive oxidation product. We established a facile synthetic route to access pure enantiomers of xylosone and confirmed that, like AI-2, the l-configuration is required for recognition by the bacterial AI-2 receptor, LuxP, whereas d-xylosone is inactive. l-xylosone is new to the human metabolome, suggesting that other chemically reactive small molecules that mediate host-microbe interactions await discovery. The identification of l-xylosone expands the AI-2 family of molecules and adds a new word to the lexicon of host-bacterial interactions.