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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）：牙周炎是一种导致牙齿脱落的牙齿支撑组织的慢性炎症性疾病。这种疾病是由一组革兰氏阴性病原体引发的炎症引起的，这些病原体以多微生物生物膜的形式定植在牙龈和牙龈下。这些生物膜中存在的病原体之一与牙周炎密切相关的是连翘单宁菌。其在发病机制中的作用已被证实