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Biosynthesis, structure and function of cell wall in Streptococcus mutans

变形链球菌细胞壁的生物合成、结构和功能

基本信息

批准号：
10576387
负责人：
Natalia Korotkova
金额：
$ 36.34万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-08 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576387
关键词：
Adherence Affect Anabolism Analytical Chemistry Antibiotics Antimicrobial Resistance Autolysin Autolysis Bacteremia Biochemical Biogenesis Biology Carbohydrates Cell Wall Cell division Cell physiology Cell surface Cellular Morphology Charge Chemical Structure Classification Collaborations Defect Dental caries Development Divalent Cations Drug Design Drug Targeting Enzymatic Biochemistry Enzymes Etiology Future Genetic Glucose Glycerol Goals Gram-Positive Bacteria Human In Vitro Infection Infective endocarditis Knowledge Light Link Mass Spectrum Analysis Mechanics Methods Microbial Biofilms Microscopy Modeling Modification Molecular Molecular Genetics Molecular Structure Morphology NMR Spectroscopy Oral cavity Outcome Outcomes Research Pathogenesis Pathway interactions Peptidoglycan Permeability Phenotype Phospholipase A2 Phospholipids Play Polysaccharides Predisposition Preparation Process Property Proteins Publishing Rattus Regulation Reporting Research Resistance Rhamnose Role Septal Region Serotyping Signal Transduction Spatial Distribution Streptococcus Streptococcus mutans Streptococcus pyogenes Structure Surface Techniques Testing Transferase Vertebral column Virulence Work antimicrobial antimicrobial drug carbohydrate biosynthesis carbohydrate structure cell envelope drug development extracellular improved inorganic phosphate insight lipoteichoic acid mutant nanomechanics neutrophil novel novel strategies pathogen quorum sensing recruit targeted treatment therapeutic target therapeutically effective

项目摘要

The cell wall of many species of Lactobacillales consists of multiple peptidoglycan layers decorated with serotype-specific polysaccharides that are characterized by the presence of rhamnose. Streptococcus mutans is a key etiological agent of human dental caries, and has also been implicated in bacteremia and infective endocarditis. Based on the chemical structures of serotype-specific carbohydrates, S. mutans is classified into serotypes c, e, f and k with approximately 70-80% of strains found in the oral cavity classified as serotype c. The serotype c-specific carbohydrate (SCC) of S. mutans is composed of a polyrhamnose backbone with α- linked glucose side-chains. Although carbohydrate structures have been reported for all S. mutans serotypes, our recent insights into the structure of these glycopolymers indicate that the functionally important modification, glycerol phosphate, was overlooked, possibly due to its loss during the purification steps. This new finding justifies a re-examination of the chemical structures of serotype-specific carbohydrates. One of the goals of the proposed study is to determine the molecular structure of SCC isolated from S. mutans using mild, non-destructive methods. Moreover, little is known about the multienzyme processes involved in attachment of the glucose side-chains to the polyrhamnose backbone of SCC and the function of the glycerol phosphate modification in S. mutans. Our preliminary findings revealed that the glycerol phosphate modification plays important roles in S. mutans morphology, autolysis, resistance to antimicrobials and biofilm formation. We propose to identify and functionally characterize the enzymes involved in glucose side-chain attachment to polyrhamnose, and investigate the molecular mechanisms underlying the functions of glycerol phosphate modification in morphology, autolysis and biofilm formation. To accomplish our goals, we will employ streptococcal genetics, in vitro enzymology, NMR spectroscopy of polysaccharides, analytical chemistry, mass spectrometric analysis of phospholipids, and various methods of microscopy including AFM-based nanomechanics. The cell wall biosynthetic machinery is an historically preferred target for the development of novel antimicrobials. In order to validate the pathway of SCC decoration with glycerol phosphate as a potential drug target, we will determine the role of this modification in a rat caries model. Successful outcomes will guide future studies of cell wall biogenesis in other important Gram-positive bacteria and the development of novel strategies to treat S. mutans infections.

许多乳酸菌的细胞壁由多个肽聚糖层组成