# Quorum Sensing Regulation of Competence and Bacteriocins in _Streptococcus pneumoniae_ and _mutans_
## 7 The Multiple Layers of Competence Regulation in _Streptococcus mutans_  
An apparent homolog of the ComCDE system of _S. pneumoniae_ identified in _S. mutans_ modulates competence [26]. Upon addition of the putative CSP to _S. mutans_ growing in peptide-rich media (i.e., Todd-Hewitt Broth (THB)), SigX activation and competence was observed, resulting in the designation of these genes as _comCDE_ in _S. mutans_[26]. However, as mentioned earlier, the _S. pneumoniae_ genome encodes an additional _comCDE_-like locus, _blpABC_/_RH_, as a regulatory system that controls production of bacteriocin-like peptides [38; 58]. In fact, the _S. mutans_ genes originally designated as _comCDE_ shares a higher degree of sequence homology to the _S. pneumoniae blp_ locus than it does with the _S. pneumoniae comCDE_ locus [29] (Table 1). It was proposed by [PERSON] et al. [27] that _S. mutans comA_ and _comB_ be renamed _nlmT_ (non-lantibiotic mutacin transporter) and _nlmE_ (_nlmT_ accessory protein), respectively, to better reflect these genes products as bacteriocin-related in function. Although the ComCDE QS pathway in _S. pneumoniae_ and the homologous _blpHR_ pathway in _S. mutans_ seemingly perform the same function of activating competence, differences in locus arrangement and gene conservation [29], kinetics of competence development [7; 19; 59], and requirements (or lack thereof) of _S. mutans_ \"ComCDE\" components for transformation [26] together suggest that _S. mutans_ harbors an alternative pathway more directly responsible for SigX activation than the apparent homolog of _comCDE_[29; 31]. The identification of an alternative regulatory pathway uncovered in the Salivarius group of _Streptococcus_ provided a likely candidate [60]. Using a transcriptomics approach, [PERSON] et al. [60] identified a peptide pheromone, ComS, encoded directly downstream of an Rgg-like transcriptional regulator, ComR, that proved to be required for SigX activity. An orthologous _comRS_ locus in _S. mutans_ was subsequently identified and found to function similarly in activating competence by controlling _sigX_ transcription [31]. For _S. mutans_, it was proposed that the pre-peptide ComS is exported to the extracellular space and processed into the active seven amino acid residue peptide pheromone, SigX-inducing peptide (XIP), by an unknown mechanism [31; 61]. In support of this model that XIP exists outside the cytoplasm, competence-inducing activity was retrieved from cell-free culture supernatants [62], the seven-residue peptide was identified by mass-spectrometry [61], and the oligopeptide permease, Opp/Ami, was required for activity, at least in CDM [31]. It is reasoned that XIP accumulates and is subsequently imported until concentrations of the peptide reach the level necessary to bind cytosolic ComR [31]. Upon binding XIP, ComR dimerizes and binds to a conserved inverted repeat (IR) sequence directly upstream of both _comS_ and _sigX_, resulting in auto-induction of the ComRS pathway and the activation of the SigX regulon, respectively [31; 63]. Similar to the induction of late genes in _S. pneumoniae_, the genes directly regulated by SigX are characterized by the separate conserved motif required for SigX binding, the cin-box ([64]) (Figure 2). It is worth noting that although the Salivarius ComRS pathway led to the discovery of the Mutans ComRS equivalent, they differ in multiple aspects, resulting in the categorization of each separately as the Type-I and Type-II ComRS systems, respectively [31; 60]. Briefly, they differ in locus arrangement in the genome and in the conserved P\({}_{comS}\)/P\({}_{sigX}\) promoter sequences (P\({}_{comR\_\text{box}}\)), but with potentially more significance they differ in the composition of the active XIP sequences and in the requirement for processing by the protease  
Figure 2: The ComRS quorum sensing (QS) pathway controls competence, and the BlpRH QS system regulates bacteriocin production in _S. mutans_ strain UA159.