# Quorum Sensing Regulation of Competence and Bacteriocins in _Streptococcus pneumoniae_ and _mutans_
## 9 Steps towards Resolving the Link between BlpRH and ComRS in _S. mutans_  
Single cell analyses have thus provided data that question the interconnections between bacteriocin and competence pathways in _S. mutans_. Though MIP-induced SigX expression is clearly occurring in peptide-rich conditions, the genetic link connecting the two pathways at this level remains elusive. Although the mechanism employed by the BlpHR pathway to influence ComRS, and thereby SigX, activity is undefined, it is now understood that SigX does have a direct impact on BlpHR signaling. It was demonstrated both by [PERSON] et al. and [PERSON] et al. (2016); [PERSON] et al. (2016) that a newly identified cin-box located immediately upstream of BlpR was required for SigX-mediated expression of the BlpRH locus and this effect was dependent upon XIP-signaling (Figure 2). This regulation of BlpR by SigX clarifies the observation that BlpR expression is up-regulated in the competent subpopulation analyzed by [PERSON] et al. (2015). However, the BlpHR pathway also affects ComRS signaling. Additional experiments from the [PERSON] et al. (2016) study demonstrated that CiB (SMU.1914c/NlmC/Mutacin V) activity is essential for a MIP-induced SigX activation in rich medium conditions, replicating previous findings by [PERSON] et al., [PERSON] et al., and [PERSON] et al. (2012); [PERSON] et al. (2012); [PERSON] et al. (2012); [PERSON] et al. (2012). This requirement for CipB appears to provide a critical piece of the puzzle as to why _comS_ is required for MIP-induced bimodal expression of SigX in peptide-rich conditions and several theories have been proposed to explain this requirement. As _cipB_ encodes a putative bacteriocin, [PERSON] et al. (2016) have predicted that CipB exerts its effects via pore formation, and that CipB pores might facilitate entry of XIP independently of Opp, thus overcoming competition for entry generated by non-specific peptides in peptide-rich media. Another mechanism was suggested by [PERSON] et al. (2012) that CipB functions intracellularly to promote the induction of competence at the transcriptional level. In their study, a _cipB_-deficient strain, grown in co-culture with the wild type strain under MIP-inducing conditions (and presumably capable of producing extracellular CipB and an ability to generate pores), was unable to exhibit an increase in transformation efficiency. Further supporting this model, microarray data showed significant decreases in expression of competence-related genes (i.e., _sigX_, _comR_ and late-competence genes) in the _cipB_-deficient strain compared to wild type when stimulated by MIP [PERSON] et al. (2012). Alternatively, secreted CipB may elicit _comS_-dependent SigX induction by mechanisms alternative to pore formation. For instance, the mechanism of action for the type AII lantibiotic salivarcin B, a Class I bacteriocin, was recently proposed to exert its effect by binding to the bacterial plasma membrane and inducing the intracellular accumulation of a bacterial cell wall precursor, resulting in cell wall thinning and atypical septal formation without penetration of the membrane [PERSON] et al. (2013). This novel mechanism of action is divergent from other type AII lantibiotics, which are commonly thought to elicit bactericidal effects via pore formation [PERSON] et al. (2013). By employing more direct approaches, such as those used by [PERSON] et al. to uncover the mechanism of action of salivuricin B, researchers may be able to determine the underlying mechanism for CipB's requirement for _S. mutans_ to become competent in peptide-rich media conditions. As mentioned previously, [PERSON] et al. (2017) also observed that CipB expression was up regulated in response to MIP, even in CDM. However, no bacteriocin activity was detected from MIP-induced _S. mutans_ cells in a bacteriocin overlay assay using _Streptococcus sanguinis_ and _Lactococcus lactis_ as indicator strains on CDM agar plates. Additionally, [PERSON] et al.