Chemical dysbiosis byproducts trigger predation via alternative activation of a peptide quorum sensor in salivarius streptococci

Cell-to-cell communication in Gram-positive bacteria is predominantly orchestrated by cytoplasmic sensors of the RRNPPA family. To date, all characterized members of this family are activated by small, unmodified peptide pheromones that mediate bacterial signaling. In the human commensal Streptococcus salivarius, the RRNPPA sensor ComR controls both competence (DNA transformation) and predation (bacteriocin production). Here, we reveal that ComR can be dually activated by its cognate peptide (XIP) and a distinct class of small organic molecules. A targeted screen of [~]200 organic compounds identified hydroxyphenylacetic acid (HPAA), a bacterial dysbiosis byproduct accumulating in human fluids, as a potent inducer of ComR. Using in vivo and in vitro approaches, we demonstrated that HPAA and structurally related carboxylic acids derived from bulky hydrophobic amino acids bind the pheromone-accommodating pocket, leading to ComR activation. Strikingly, while XIP-mediated activation is transient and regulates both competence and predation, HPAA induces a sustained, predation-oriented response. Furthermore, we showed that Porphyromonas gingivalis, an oral pathogen, produces sufficient (H)PAA quantity to trigger bacteriocin production in S. salivarius, revealing a previously unrecognized chemical interplay between oral microbiota members. These findings highlight the remarkable versatility of cytoplasmic sensors to integrate diverse environmental cues, shedding new light on bacterial peptide-based communication and microbial homeostasis in the human microbiome. IMPORTANCEBacterial communication through quorum sensing (QS) is crucial for coordinating key physiological processes. While QS in Gram-positive bacteria has been predominantly associated with peptide pheromones, our study uncovers an undescribed alternative signaling mechanism. We demonstrate that ComR, a cytoplasmic receptor of the RRNPPA family, can be activated by its canonical peptide signal and by small organic molecules derived from the anaerobic breakdown of hydrophobic amino acids. This alternative activation pathway enhances the ability of S. salivarius to respond to microbial dysbiosis, maintaining ecological balance in the digestive tract. Beyond revealing a novel layer of bacterial communication, our findings suggest that many RRNPPA-family receptors previously considered "orphan" may respond to yet-undiscovered chemical signals. This work expands our understanding of bacterial sensing and opens new avenues for modulating microbial interactions in health and disease.