Novel Mechanisms of Peptidoglycan Synthesis in Tannerella forsythia

连翘坦纳菌肽聚糖合成的新机制

基本信息

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
项目类别：
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

项目摘要

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）：牙周炎是牙齿支持组织的一种慢性炎症性疾病，会导致牙齿脱落。该疾病是由一组革兰氏阴性病原体引发的炎症引起的，这些病原体以多种微生物生物膜的形式定殖在牙龈和龈下位置。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连翘坦纳氏菌。其在发病机制中的作用已被证实感染细菌后在动物模型中繁殖疾病（牙周骨破坏）。独特的是，连翘需要外源 MurNAc（一种必需的肽聚糖氨基糖）才能生长。迄今为止，尚未在其他病原体中观察到这种情况，但这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，尽管其明显能够利用外源提供的 MurNAc，但 Tannerella 基因组也缺乏其他细菌中存在的 PTS 型 MurNAc 转运蛋白的同源物。这些独特的特征表明细菌中存在摄取和利用 MurNAc 的新机制。令人惊讶的是，如果含有唾液酸的唾液酸糖蛋白，连翘可以在没有 MurNAc 的情况下在体外生物膜中生长而是进行补充。我们预测，在体内，细菌对 MurNAc 的需求是通过清除共居细菌在细胞壁回收过程中和生物膜生长过程中由唾液酸合成 MurNAc 释放的 MurAP 肽和 MurNAc 来满足的，而 MurNAc 最有可能在体内通过以下作用获得：宿主糖蛋白上的细菌唾液酸酶。因此，本研究的目的是明确连翘转运外源 MurNAc 进行肽聚糖合成的机制（目标 1），并发现细菌中唾液酸合成 MurNAc 的代谢途径（目标 2）。总的来说，这项研究将提供对连翘与 MurNAc 吸收/利用相关的独特生理学的基本了解，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针对 MurNAc 吸收/利用途径的新抗菌剂，以控制连翘生长。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需求的其他细菌也很有价值。