# Quorum Sensing Regulation of Competence and Bacteriocins in _Streptococcus pneumoniae_ and _mutans_
## 10 Additional Inputs Regulating Competence in _S. mutans_  
Even as the intricacies of competence signaling by the known direct regulators (i.e., ComR and SigX) are still under investigation, multiple additional QS pathways have been shown to modulate natural transformation in _S. mutans_. Examples of these QS systems include the CiaRH TCST, important for Mutacin I activity, tolerance to oxidative stress, acid tolerance, and biofilm formation ([PERSON] et al., 2017; [PERSON] et al., 2017; [PERSON] et al., 2017); the HdrRM locus, involved in Mutacin IV expression ([PERSON] et al., 2017); and the RcrRPQ operon, implicated in acid tolerance and regulation of intracellular (p)ppGpp pools ([PERSON] et al., 2017; [PERSON] et al., 2017; [PERSON] et al., 2017) (Figure 2). Cumulatively, the effect of these pathways on competence strongly suggests the importance of _S. mutans_' ability to integrate environmental cues to effectively undergo natural transformation and bacteriocin expression. Expression of the entire set of transformasome-related genes is an energetically costly endeavor. Similarly, in _S. pneumoniae_, additional input pathways contribute to competence regulation, including the pneumococcal ortholog of the CiaRH TCST ([PERSON] et al., 2017) and the luxS QS pathway important for iron-dependent biofilm formation ([PERSON] et al., 2017). Therefore, _S. mutans_ and _S. pneumoniae_ appear to have evolved complex sensory mechanisms to maximize the benefit of acquiring eDNA. In the context of these organisms' lifestyle within the oral and nasopharyngeal cavities, these mechanisms might provide competitive advantages against other commensals and/or pathogens by allowing the coordinated expression of bacteriocins to lyse competitors, yielding a valuable source of eDNA. Uncovering Conservation Patterns of Competence and Bacteriocin QS Pathways in _Streptococcus_: Further Indications of Regulatory Interconnectedness? As additional Streptococcus genomes are sequenced, unveiling putative competence pathways (i.e., ComCDE, ComRS Type I, II, and III), more opportunities have arisen to investigate the potential of natural transformation in these species. For example, the identification of the ComRS pathway in _S. mutans_ and _Streptococcus thermophilus_ facilitated the discovery of orthologs in _S. pyogenes_, _Streptococcus infantarius_, _Streptococcus macedonius_, and _Streptococcus suis_([PERSON] et al., 2012; [PERSON] et al., 2013; [PERSON] et al., 2014). While each of these species expresses SigX in response to treatment with the respective XIP, species within the Pyogenic group, exemplified by _S. pyogenes_, have failed to transform under these conditions ([PERSON] et al., 2012). However, when _S. pyogenes_ was grown as a biofilm on human keratinocytes, in the absence of exogenous XIP, natural transformation was observed, albeit at low efficiency ([PERSON] et al., 2017). These results suggest that unknown environmental cues or signals may provide a yet-to-be identified regulatory input into the pyogenic SigX regulon, possibly exerting a suppressive effect on the development of competence ([PERSON] et al., 2012). As an alternative explanation, the ComRS pathway may have evolved a separate function in the Pyogenics. This scenario is unlikely, as ComRS activity was demonstrated to directly activate SigX transcription and this conserved alternative sigma factor is the main effector of competence in all known transformable _Streptococcus_ species ([PERSON] et al., 2017; [PERSON] et al., 2012; [PERSON] et al., 2013; [PERSON] et al., 2014; [PERSON] et al., 2014; [PERSON] et al., 2014). However, it is prudent to consider the possibility that homologous pathways operating upstream of SigX in one species may have diverged in function in another species, best represented by the ComC-regulated QS pathway of _S. pneumoniae_ and the homologous pathway in _S. mutans_ regulated by MIP. Recognition of such potential caveats, discussed in detail in the review by [PERSON] et al.