Structural Investigations of Biofilm Matrices for Novel Antibiofilm Strategies

用于新型抗生物膜策略的生物膜基质的结构研究

基本信息

批准号：
10529341
负责人：
JOHN W BRADY
金额：
$ 29.44万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10529341
关键词：
Anabolism Antibiotic Resistance Antibiotics Architecture Bacteria Bacterial Antibiotic Resistance Bacterial Infections Bacterial Polysaccharides Binding Biophysics Burkholderia Burkholderia cepacia complex Cell Communication Cells Chemicals Clinical Computer Models Computer Simulation Developing Countries Development Funding Gel Glycopeptides Goals Growth Hospitalization Hydration status Hydrophobicity Infant Infection Investigation Klebsiella Klebsiella pneumoniae Knowledge acquisition Lipids Lung infections Maintenance Medical Meningitis Methods Microbial Biofilms Modeling Molecular Molecular Conformation Molecular Weight Morphology Oligosaccharides Patients Peptides Phage Display Pneumonia Polymers Polysaccharides Population Prevention Procedures Research Resistance Rhamnose Role Stimulus Structure Structure-Activity Relationship System Testing Therapeutic Therapeutic Agents United States National Institutes of Health Urinary tract infection Vertebral column Water antimicrobial cystic fibrosis infection cystic fibrosis patients design experimental study extracellular intermolecular interaction macromolecule molecular dynamics molecular mass molecular mechanics novel novel strategies novel therapeutics opportunistic pathogen prevent quorum sensing resistant strain synergism

项目摘要

Project Summary/Abstract This project will combine molecular dynamics simulations and other types of molecular mechanics calculations with various experimental methods to characterize the biofilms formed by opportunistic pathogen species belonging to the Burkholderia cepacia Complex (BCC) and by Klebsiella pneumoniae. Bacterial biofilms constitute a serious concern in infections since they confer increased resistance towards antimicrobial therapies. In biofilms, bacteria live within a hydrated matrix composed of various macromolecules, and in particular polysaccharides, which are primarily responsible for its formation. Understanding the details of biofilm matrix structure can be of significant utility in designing novel strategies for treating infections. This is the main objective of this proposal, which is a request for the continuation of a currently funded NIH study (GM123283) based on the results acquired in this current project characterizing the structure of polysaccharides produced by species of the BCC and K. pneumoniae. These polymers contain clusters of non-polar rhamnose residues that confer a less polar character to the chains, suggesting the possible formation of hydrophobic juncture zones in the gel- like structures of their biofilm matrices, and possibly constituting targets for biofilm disruption. On the basis of the results already achieved, the following research lines will be explored both experimentally and by computer modelling: 1) Structurally different rhamnose-rich polysaccharides produced by Burkholderia and Klebsiella will be studied to investigate their morphology and aggregation tendency, with the objective of modeling their biofilm matrix architectures. 2) The interactions of matrix polysaccharides with molecules participating in quorum sensing systems will be studied to define the role of the matrix in cell-cell communication. 3) The possibility of weakening matrix architecture by using specific agents will be explored using three systems, all designed to target matrix junction zones: i) oligosaccharides containing rhamnose residues; ii) specific peptides which have already been found, by means of phage display procedures, to bind bacterial polysaccharides; iii) synthetic glycopeptides obtained binding rhamnose residues to selected peptides investigated in point ii). Changes in biofilm matrix morphologies will be studied by adding these test molecules to bacterial cultures.

项目摘要/摘要该项目将结合分子动力学模拟和其他类型的分子力学计算用各种实验方法来表征机会性病原体形成的生物膜属于Burkholderia cepacia Complex（BCC）和Klebsiella肺炎。细菌生物膜由于它们赋予对抗菌疗法的耐药性，因此对感染构成了严重关注。在生物膜中，细菌生活在由各种大分子组成的水合基质中，尤其是多糖主要负责其形成。了解生物膜矩阵的细节在设计治疗感染的新型策略方面，结构可能具有重要的效用。这是主要目标在此提案中，这是基于目前资助的NIH研究（GM123283）的要求在当前项目中获得的结果表征了物种产生的多糖结构 BCC和K.肺炎。这些聚合物包含赋予A的非极性鼠李糖残基的簇链的极性较小，表明凝胶中可能形成疏水连接区就像其生物膜矩阵的结构一样，可能构成生物膜破坏的靶标。根据已经达到的结果，将在实验中探索以下研究行并通过计算机建模： 1）将研究由Burkholderia和Klebsiella生产的结构上不同的富含鼠射糖的多糖研究其形态和聚集趋势，目的是建模其生物膜基质体系结构。 2）基质多糖与参与法定感应系统的分子的相互作用将是研究以定义矩阵在细胞 - 细胞通信中的作用。 3）使用三个系统探索通过使用特定代理来削弱矩阵架构的可能性，所有旨在靶向矩阵连接区域：i）含有鼠李糖残基的寡糖； ii）具体通过噬菌体显示程序已经发现已经结合细菌的肽多糖； iii）合成糖肽获得了与选定肽的结合鼠李糖残基在第二点进行了调查）。通过添加这些测试分子，将研究生物膜基质形态的变化到细菌培养物。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Bep gene cluster in Burkholderia cenocepacia H111 codes for a water-insoluble exopolysaccharide essential for biofilm formation.

新洋葱伯克霍尔德菌 H111 中的 Bep 基因簇编码生物膜形成所必需的水不溶性胞外多糖。

DOI：
10.1016/j.carbpol.2022.120318
发表时间：
2023
期刊：
Carbohydrate polymers
影响因子：
11.2
作者：
Bellich,Barbara;Terán,LucreciaC;Fazli,MagnusM;Berti,Francesco;Rizzo,Roberto;Tolker-Nielsen,Tim;Cescutti,Paola
通讯作者：
Cescutti,Paola

Ramachandran conformational energy maps for disaccharide linkages found in Burkholderia multivorans biofilm polysaccharides.

DOI：
10.1016/j.ijbiomac.2019.11.037
发表时间：
2020-01-15
期刊：
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
影响因子：
8.2
作者：
Jou, Ining A.;Caterino, Marco;Schnupf, Udo;Rizzo, Roberto;Cescutti, Paola;Brady, John W.
通讯作者：
Brady, John W.

The biofilm of Burkholderia cenocepacia H111 contains an exopolysaccharide composed of l-rhamnose and l-mannose: Structural characterization and molecular modelling.

DOI：
10.1016/j.carres.2020.108231
发表时间：
2021-01
期刊：
Carbohydrate research
影响因子：
3.1
作者：
通讯作者：

Proteomic Studies of the Biofilm Matrix including Outer Membrane Vesicles of Burkholderia multivorans C1576, a Strain of Clinical Importance for Cystic Fibrosis.

DOI：
10.3390/microorganisms8111826
发表时间：
2020-11-19
期刊：
Microorganisms
影响因子：
4.5
作者：
Terán LC;Distefano M;Bellich B;Petrosino S;Bertoncin P;Cescutti P;Sblattero D
通讯作者：
Sblattero D