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

• 批准号: 10322428
• 负责人: JOHN W BRADY
• 金额: $ 31.58万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322428
• 关键词: 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; Hydration status; Hydrophobicity; Infant; Infection; Investigation; Klebsiella; Klebsiella pneumoniae; Knowledge; 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; base; 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

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.

项目总结/摘要 该项目将联合收割机分子动力学模拟和其他类型的分子力学计算结合起来 利用各种实验方法来表征由条件致病菌物种形成的生物膜 属于洋葱伯克霍尔德氏菌复合体（BCC）和肺炎克雷伯氏菌。细菌生物膜 在感染中构成严重问题，因为它们赋予对抗微生物疗法增加的抗性。 在生物膜中，细菌生活在由各种大分子组成的水合基质中，特别是 多糖，这是主要负责其形成。了解生物膜基质的细节 结构在设计治疗感染的新策略中具有重要的实用性。这是主要目标 这是一项要求继续进行目前资助的NIH研究（GM 123283）的请求， 本项目获得的结果表征了物种产生的多糖的结构， BCC和K.肺炎。这些聚合物含有非极性鼠李糖残基的簇，其赋予聚合物分子链上的非极性鼠李糖残基。 链的极性较低，表明凝胶中可能形成疏水接合区- 类似于它们的生物膜基质的结构，并且可能构成生物膜破坏的靶。 在已经取得的成果的基础上，将对以下研究路线进行实验性探索， 通过计算机建模： 1)将研究伯克霍尔德氏菌和克雷伯氏菌产生的结构不同的富含鼠李糖的多糖 研究它们的形态和聚集趋势，目的是模拟它们的生物膜基质 建筑 2)基质多糖与参与群体感应系统的分子之间的相互作用将是 研究以确定基质在细胞间通讯中的作用。 3)通过使用特定的代理人削弱矩阵架构的可能性将使用三个系统进行探索， 全部设计为靶向基质连接区：i）含有鼠李糖残基的寡糖; ii）特异性 已经通过噬菌体展示方法发现的结合细菌的肽 多糖; iii）将鼠李糖残基结合至所选肽而获得的合成糖肽 在第二点中进行了调查）。生物膜基质形态的变化将通过加入这些测试分子进行研究 到细菌培养。