Carbohydrate and PepO control bimodality in competence development by Streptococcus mutans

Summary In Streptococcus mutans, the alternative sigma factor ComX controls entry into genetic competence. Competence stimulating peptide (CSP) induces bimodal expression of comX, with only a fraction of the population becoming transformable. Curiously, the bimodality of comX is affected by peptides in the growth medium and by carbohydrate source. CSP elicits bimodal expression of comX in media rich in small peptides, but CSP elicits no response in defined media lacking small peptides. In addition, growth on certain sugars increases the proportion of the population that activates comX in response to CSP. By investigating the connection between media and comX bimodality, we find evidence for two mechanisms that modulate transcriptional positive feedback in the ComRS system, where comX bimodality originates. We find that the endopeptidase PepO suppresses the ComRS feedback loop, most likely by degrading the XIP/ComS feedback signal. Deletion of pepO eliminates comX bimodality, leading to a unimodal comX response to CSP in both defined and complex media. We also find that CSP stimulates the ComRS feedback system by upregulating comR in a carbohydrate source‐dependent fashion. Our data provide mechanistic insight into how S. mutans regulates bimodality and explain the puzzle of growth medium effects on competence induction by CSP. The CSP peptide induces genetic competence only in a fraction of S. mutans cells, and in peptide‐rich growth media. We show that the endopeptidase PepO is responsible for preventing a population‐wide competence response. Our data indicate that PepO suppresses positive transcriptional feedback in the ComRS system, which controls comX activity and gives rise to the bimodal and medium‐dependent competence. In addition, we show that some carbohydrates stimulate ComRS feedback by enhancing transcription of comR. These findings reveal mechanisms behind some striking properties of the S. mutans competence pathway.