Novel Mechanisms of Peptidoglycan Synthesis in Tannerella forsythia

连翘坦纳菌肽聚糖合成的新机制

• 批准号: 8845539
• 负责人: Ashu Sharma
• 金额: $ 19.94万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-05 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8845539
• 关键词: Acetylglucosamine; Amino Sugars; Animal Model; Bacteria; Biochemical Pathway; Cell Wall; Cell surface; Cells; Characteristics; Chronic; Complex; Computer Simulation; Data; Disease; Endodontics; Enzymes; Escherichia coli; Forsythia; Funding; Gene Cluster; Gene Expression Profile; Gene Expression Profiling; Genes; Genome; Genomic Library; Gingiva; Glycoproteins; Gram-Negative Bacteria; Growth; Health; Homologous Gene; Human; In Vitro; Infection; Inflammation; Inflammatory; Isomerase; Knowledge; Label; Lactamase; Lead; Location; Membrane; Metabolic; Metabolic Pathway; Metabolism; Microbial Biofilms; Muramic Acid; N-acetylmuramic acid; Neuraminidase; Nutritional Requirements; Operon; Oral cavity; Orthologous Gene; Pathogenesis; Pathway interactions; Peptidoglycan; Periodontal Diseases; Periodontitis; Phosphotransferases; Physiological; Physiology; Porphyromonas gingivalis; Production; Proteins; Radiolabeled; Recycling; Reporter; Reproduction; Role; Sialic Acids; Sialoglycoproteins; System; Testing; Tissues; Tooth Diseases; Tooth Loss; Treponema denticola; anhydro-N-acetylmuramic acid; antimicrobial; antimicrobial drug; base; bone; design; in vivo; inhibitor/antagonist; insight; mimetics; mutant; novel; oral bacteria; pathogen; permease; radiotracer; salivary mucins; sialic acid permease; small molecule; sugar; transcriptome sequencing; uptake

DESCRIPTION (provided by applicant): Periodontitis is a chronic inflammatory disease of the tooth supporting tissue that leads to tooth loss. The disease results from the inflammation triggered by a group of Gram-negative pathogens that colonize the gingival and sub-gingival locations as polymicrobial biofilms. One of the pathogens present in these biofilms and strongly implicated in periodontitis is Tannerella forsythia. Its role in pathogenesis has been confirmed by reproduction of the disease (periodontal bone destruction) in animal models following infection with the bacterium. Uniquely, T. forsythia requires exogenous MurNAc, an essential peptidoglycan aminosugar, for growth. To date, this has not been observed for other pathogens but is likely due to the absence of genes encoding the key enzyme in its genome for the de novo synthesis of MurNAc from simple sugars. Moreover, despite its clear ability to utilize exogenously supplied MurNAc, the Tannerella genome also lacks homologs of PTS-type MurNAc transporters present in other bacteria. These unique characteristics suggest that novel mechanisms for MurNAc uptake and utilization exist in the bacterium. Surprisingly, T. forsythia can grow in in vitro biofilms in the absence of MurNAc if sialic acid-containing sialoglycoproteins are supplemented instead. We predict that in vivo the MurNAc requirements of the bacterium are fulfilled by scavenging muropeptides and MurNAc released by cohabiting bacteria during their cell wall recycling and during biofilm growth by MurNAc synthesis from sialic acid, which is most likely made available in vivo by the action of bacterial sialidase(s) on host glycoproteins. Thus, the objectives of this study are to define the mechanisms by which T. forsythia transports exogenous MurNAc for peptidoglycan synthesis (Aim1), and discover the metabolic pathways by which MurNAc is synthesized from sialic acid in the bacterium (Aim 2). Overall, this study will provide a basic understanding of the unique physiology of T. forsythia in relation to MurNAc uptake/utilization as well as novel insights into the nutritional requirements of the bacterium in the human oral cavity. This knowledge will aid in designing new antimicrobial agents targeting MurNAc uptake/utilization pathways to control T. forsythia growth. Moreover, the information will be valuable for understanding other bacteria which have not yet been cultivated/identified but might have similar physiological requirements.

描述（由申请人提供）：牙周炎是一种导致牙齿脱落的牙齿支持组织的慢性炎症性疾病。该疾病是由一组革兰氏阴性病原体引发的炎症引起的，这些病原体作为多微生物生物膜定殖于牙龈和龈下位置。存在于这些生物膜中并与牙周炎密切相关的病原体之一是坦纳氏菌。其在发病机制中的作用已被证实， 在细菌感染后的动物模型中疾病的再现（牙周骨破坏）。独特的，T。该菌生长需要外源性MurNAc，一种必需的肽聚糖氨基糖。到目前为止，这还没有在其他病原体中观察到，但可能是由于其基因组中缺乏编码从单糖从头合成MurNAc的关键酶的基因。此外，尽管其具有利用外源提供的MurNAc的明确能力，但坦纳菌基因组也缺乏存在于其他细菌中的PTS型MurNAc转运蛋白的同源物。这些独特的特征表明，MurNAc的吸收和利用的新机制存在于细菌中。令人惊讶的是，T。如果含唾液酸的唾液糖蛋白 而是补充。我们预测，在体内的MurNAc的细菌的需求是满足清除的胞肽和MurNAc释放的共存细菌在其细胞壁再循环和生物膜生长过程中的MurNAc从唾液酸合成，这是最有可能在体内提供的作用，细菌唾液酸酶对宿主糖蛋白。因此，本研究的目的是确定T。该菌转运外源性MurNAc用于肽聚糖合成（Aim 1），并发现了MurNAc在细菌中由唾液酸合成的代谢途径（Aim 2）。总的来说，这项研究将提供一个基本的了解独特的生理T。关于MurNAc的摄取/利用以及对人类口腔中细菌的营养需求的新见解。这些知识将有助于设计新的抗菌剂靶向MurNAc的吸收/利用途径，以控制T。生长发育。此外，这些信息对于了解尚未培养/鉴定但可能具有类似生理要求的其他细菌将是有价值的。