Non-peptide dysbiosis metabolites reprogram a peptide quorum-sensing receptor to induce sustained predation in beneficial streptococci.

Cytoplasmic receptors of the RRNPPA superfamily mediate peptide-based quorum sensing in Gram-positive bacteria and are thought to be activated exclusively by short, unmodified pheromones. Here, we show that the RRNPPA regulator ComR in the human commensal Streptococcus salivarius can also be activated by a distinct class of non-peptide metabolites. A screen of ~200 organic compounds identified hydroxyphenylacetic acid (HPAA)-a microbial dysbiosis-associated catabolite-as a potent activator of ComR. Using biochemical and genetic approaches, we demonstrate that HPAA and related aromatic carboxylic acids bind the canonical pheromone pocket and induce sustained expression of predatory bacteriocins, while bypassing the competence program triggered by the native peptide signal (XIP). We further show that the oral pathogen Porphyromonas gingivalis produces physiologically relevant amounts of (H)PAA, enabling metabolite-driven activation of predation in S. salivarius. These findings reveal an unexpected capacity of RRNPPA receptors to sense both peptide and metabolite cues, uncovering a chemical mode of interspecies communication that links dysbiosis to predatory behavior in the oral microbiome.