Coordinated Regulation of the EII and Operons of Streptococcus mutans by Global and Fructose-Specific Pathways.

The glucose/mannose-phosphotransferase system (PTS) permease EII encoded by in the dental caries pathogen has a dominant influence on sugar-specific, CcpA-independent catabolite repression (CR). Mutations in affect energy metabolism and virulence-associated traits, including biofilm formation, acid tolerance, and competence. Using promoter::reporter fusions, expression of the and the operons, encoding a transcriptional regulator, a fructose-1-phosphate kinase and a fructose-PTS permease EII, respectively, was monitored in response to carbohydrate source and in mutants lacking CcpA, FruR, and components of EII Expression of genes for EII and EII was directly regulated by CcpA and CR, as evinced by and methods. Unexpectedly, not only was the operon negatively regulated by FruR, but also so was Carbohydrate transport by EII had a negative influence on expression of but not In agreement with the proposed role of FruR in regulating these PTS operons, loss of or substantially altered growth on a number of carbohydrates, including fructose. RNA deep sequencing revealed profound changes in gene regulation caused by deletion of or Collectively, these findings demonstrate intimate interconnection of the regulation of two major PTS permeases in and reveal novel and important contributions of fructose metabolism to global regulation of gene expression. The ability of and other streptococcal pathogens to survive and cause human diseases is directly dependent upon their capacity to metabolize a variety of carbohydrates, including glucose and fructose. Our research reveals that metabolism of fructose has broad influences on the regulation of utilization of glucose and other sugars, and mutants with changes in certain genes involved in fructose metabolism display profoundly different abilities to grow and express virulence-related traits. Mutants lacking the FruR regulator or a particular phosphofructokinase, FruK, display changes in expression of a large number of genes encoding transcriptional regulators, enzymes required for energy metabolism, biofilm development, biosynthetic and degradative processes, and tolerance of a spectrum of environmental stressors. Since fructose is a major component of the modern human diet, the results have substantial significance in the context of oral health and the development of dental caries.