and Modulate Production of Mutanocyclin and Reutericyclins in Streptococcus mutans B04Sm5.

Streptococcus mutans is considered a primary etiologic agent of dental caries, which is the most common chronic infectious disease worldwide. S. mutans B04Sm5 was recently shown to produce reutericyclins and mutanocyclin through the biosynthetic gene cluster and to utilize reutericyclins to inhibit the growth of neighboring commensal streptococci. In this study, examination of S. mutans and phylogeny suggested evolution of an ancestral S. mutans into three lineages within one S. mutans clade and then horizontal transfer of to other S. mutans clades. The roles of the mucG and mucH transcriptional regulators and the mucI transporter were also examined. was demonstrated to encode a transcriptional activator of . deletion reduced production of mutanocyclin and reutericyclins and eliminated the impaired growth and inhibition of neighboring streptococci phenotypes, which are associated with reutericyclin production. Δ had increased mutanocyclin and reutericyclin production, which impaired growth and increased the ability to inhibit neighboring streptococci. However, deletion of also caused reduced expression of , , and Deletion of reduced mutanocyclin and reutericylin production but enhanced growth, suggesting that may not transport reutericyclin as its homolog does in Limosilactobacillus reuteri. Further research is needed to determine the roles of and and to identify any cofactors affecting the activity of the and regulators. Overall, this study provided pangenome and phylogenetic analyses that serve as a resource for S. mutans research and began elucidation of the regulation of reutericyclins and mutanocyclin production in S. mutans. S. mutans must be able to outcompete neighboring organisms in its ecological niche in order to cause dental caries. S. mutans B04Sm5 inhibited the growth of neighboring commensal streptococci through production of reutericyclins via the biosynthetic gene cluster. In this study, an S. mutans pangenome database and updated phylogenetic tree were generated that will serve as valuable resources for the S. mutans research community and that provide insights into the carriage and evolution of S. mutans The MucG and MucH regulators, and the MucI transporter, were shown to modulate production of reutericyclins and mutanocyclin. These genes also affected the ability of S. mutans to inhibit neighboring commensals, suggesting that they may play a role in S. mutans virulence.