Utilization of N-acetylglucosamine by Streptococcus mutans and its regulation

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 DESCRIPTION (provided by applicant): Remarkably complex microbial communities colonize human oral cavity, and the composition and biochemical activities of the communities differ in healthy humans compared with individuals with dental caries or periodontal diseases. Interactions between oral biofilms and host environment warrant extensive study to better understand the initiation and progression of diseases. Carbohydrates in the human diet, and those provided by host secretions, host cells and microorganisms provide essential carbon and energy sources to many bacterial taxa that colonize human tooth surface. This is especially true for the lactic acid bacteria (LAB), which depend almost entirely on carbohydrates for energy and acid production. Glucosamine (GlcN) and N- acetylglucosamine (GlcNAc) are among the most abundant naturally-occurring sugars on the planet, and are catabolized by many bacterial species as a source of both carbon and nitrogen. In the absence of these amino sugars, bacteria also synthesize GlcN-6-P from fructose-6-P and glutamine for cell wall biogenesis. Despite the ubiquity of these amino sugars in the oral cavity, there have been very few studies regarding their utilization by the oral microbiota, and in particular by dental caries pathogens. Here, we present new data on the regulation and role in physiologic homeostasis of GlcN and GlcNAc utilization and biosynthesis in the major dental caries pathogen, Streptococcus mutans. Importantly, we show that the regulatory mechanisms governing the endogenous production of GlcN-6-P are different from paradigm models, such as Bacillus subtilis and Escherichia coli. Specifically, we have demonstrated that the genes responsible for GlcNAc catabolism encoding GlcNAc-6-P deacetylase (NagA) and GlcN-6-P deaminase (NagB), are negatively regulated by the GntR/HutC-family regulator NagR. While NagR-dependent regulation of nagAB is fairly common, we also discovered that the gene encoding the enzyme responsible for producing GlcN-6-P, GlmS, is also under direct control of NagR; a highly unusual finding since NagB catabolizes, but GlmS produces, GlcN-6-P. Moreover, the RNA-based pathways for control of glmS translational efficiency in E. coli or of mRNA stability in B. subtilis do not appear to be present in S. mutans. On the basis of these observations, we propose 1) to begin to dissect the molecular mechanisms maintaining the critical balance between NagB and GlmS activities and 2) to explore in more detail the physiologic and ecological benefits of the consumption of GlcNAc by S. mutans. The knowledge gained from these studies will provide critical information needed to understand amino sugar metabolism by S. mutans and related oral bacteria, which could lead to improved control of the pathogenic potential of the oral flora. In addition, many lactobacilli, group A streptococci, and Streptococcus pneumoniae, appear to share some key features in glmS regulation with S. mutans, so these investigations are of high relevance to a group of important human pathogens and commensals.