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

## TL;DR

A common oral bacterium can detect chemical signals from dysbiosis and use them to trigger long-term antibacterial behavior.

## Contribution

Discovery that a peptide receptor can also sense non-peptide metabolites to drive predation in commensal streptococci.

## Key findings

- Hydroxyphenylacetic acid (HPAA) activates ComR receptor in Streptococcus salivarius.
- HPAA induces sustained bacteriocin expression while bypassing the competence program.
- Porphyromonas gingivalis produces HPAA at levels sufficient to activate predation in S. salivarius.

## Abstract

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.

Microbial dysbiosis alters chemical cues in the oral microbiome, but how commensals sense these changes is unclear. This study shows that Streptococcus salivarius detects dysbiosis metabolites and repurposes a peptide quorum-sensing receptor to drive sustained antibacterial predation, revealing a new form of interspecies chemical communication.