Utilization of N-acetylglucosamine by Streptococcus mutans and its regulation

变形链球菌对N-乙酰氨基葡萄糖的利用及其调控

• 批准号: 8974827
• 负责人: Lin Zeng
• 金额: $ 11.25万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974827
• 关键词: Acids; Amino Sugars; Anabolism; Bacillus subtilis; Bacteria; Biochemical; Biogenesis; Biological Assay; Carbohydrates; Carbon; Catabolism; Cell Wall; Cells; Communicable Diseases; Communities; Complex; Consumption; Coupled; Data; Deacetylase; Deaminase; Dental caries; Development; Diet; Disease Progression; Ecology; Energy-Generating Resources; Environment; Environmental Impact; Enzymes; Equilibrium; Escherichia coli; Family; Foundations; Fructose; Future; Gene Expression; Generations; Genes; Genetic; Glucosamine; Glucose; Glutamine; Goals; Growth; Health; Homeostasis; Human; Individual; Investigation; Knowledge; Lactobacillus; Lead; Mannose; Metabolism; Microbial Biofilms; Modeling; Molecular; Molecular Biology; Molecular Profiling; Nitrogen; Oral; Oral cavity; Oral health; Organism; Pathway interactions; Peptidoglycan; Periodontal Diseases; Physiological; Physiology; Pilot Projects; Planets; Play; Principal Investigator; Process; Production; Property; Protein S; RNA; Regulation; Research; Role; Signal Transduction; Site; Source; Streptococcus mutans; Streptococcus pneumoniae; Streptococcus pyogenes; Taxon; Virulence; Virulence Factors; Work; bacterial fitness; base; career; cariogenic bacteria; combat; design; differential expression; fitness; gene discovery; improved; lactic acid bacteria; mRNA Stability; microbial; microbial community; microbiota; microorganism; mutant; new therapeutic target; novel therapeutics; oral bacteria; oral biofilm; pH Homeostasis; pathogen; promoter; response; sugar; tool; tooth surface; trait

 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.

 描述(申请人提供)：非常复杂的微生物群落在人类口腔中定居，与患有龋齿或牙周病的人相比，健康人的群落组成和生化活动不同。口腔生物膜与宿主环境之间的相互作用值得广泛研究，以更好地了解疾病的发生和发展。人类饮食中的碳水化合物，以及由宿主分泌物、宿主细胞和微生物提供的碳水化合物，为许多定植于人类牙齿表面的细菌提供了必要的碳和能源来源。对于乳酸菌(LAB)来说尤其如此，它们几乎完全依赖碳水化合物来提供能量和产酸。氨基葡萄糖(GlcN)和N-乙酰氨基葡萄糖(GlcNAc)是地球上含量最丰富的天然糖，作为碳和氮的来源，许多细菌都能分解它们。在缺乏这些氨基糖的情况下，细菌也可以从果糖-6-P和谷氨酰胺合成GlcN-6-P，用于细胞壁的生物发生。尽管这些氨基糖在口腔中无处不在，但关于它们被口腔微生物区系利用的研究很少，特别是对龋病病原体的利用。在这里，我们提供了关于主要龋病病原体变形链球菌中GlcN和GlcNAc的利用和生物合成的调节和在生理动态平衡中的作用的新数据。重要的是，我们表明控制GlcN-6-P内源生产的调节机制不同于范式模型，如枯草芽孢杆菌和大肠杆菌。具体地说，我们已经证明，编码GlcNAc-6-P脱乙酰酶(NAGA)和GlcN-6-P脱氨酶(NAGB)的GlcNAc分解代谢相关基因受到GntR/HutC-家族调控因子NAGR的负调控。虽然NAGR对nagAB的调节是相当普遍的，但我们也发现编码负责产生GlcN-6-P的酶GLMS的基因也受到NAGR的直接控制；这是一个非常不寻常的发现，因为NAGB分解代谢，但GLMS产生GlcN-6-P。此外，基于RNA的途径控制GLMS在大肠杆菌中的翻译效率或在枯草杆菌中的mRNA稳定性似乎不存在于变形链球菌中。在这些观察的基础上，我们建议1)开始剖析维持NAGB和GLMS活性之间关键平衡的分子机制，2)更详细地探索变形链球菌消耗GlcNAc的生理和生态效益。从这些研究中获得的知识将为了解变形链球菌和相关口腔细菌的氨基糖代谢提供必要的关键信息，这可能有助于改善对口腔菌群致病潜力的控制。此外，许多乳杆菌、A组链球菌和肺炎链球菌似乎与变形链球菌在GLMS调控方面具有一些关键特征，因此这些研究与一组重要的人类病原体和共生菌具有很高的相关性。