Integration of redox-balancing mechanisms in Pseudomonas aeruginosa biofilms

铜绿假单胞菌生物膜中氧化还原平衡机制的整合

• 批准号: 9902315
• 负责人: Lars Dietrich
• 金额: $ 39.96万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-20 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902315
• 关键词: Address; Aerobic; Affect; Agar; Air; Anaerobic Bacteria; Antibiotic Resistance; Antibiotics; Antibodies; Antimicrobial susceptibility; Bacteria; Bacterial Infections; Behavior; Binding; Biochemical; Biological Assay; Carbon; Cells; Chemicals; Communities; Complement; Crystallization; Cues; Development; Disease; Drug resistance; Electrons; Energy-Generating Resources; Enzymes; Equilibrium; Extracellular Matrix; Extracellular Structure; Fluorescence Microscopy; Generations; Genetic; Goals; Growth; Guanosine Monophosphate; Homeostasis; Hospitals; Image; Infection; Investigation; Isomerism; Lactate Dehydrogenase; Link; Liquid substance; Lung infections; Mediating; Mediator of activation protein; Metabolic; Metabolism; Microbial Biofilms; Microscopic; Microscopy; Modeling; Molecular; Morphogenesis; Morphology; Mus; Mycoses; Oxidants; Oxidation-Reduction; Oxides; Oxygen; Pathogenicity; Pathway interactions; Periodicity; Phenazines; Physiological; Physiology; Predisposition; Production; Proteins; Pseudomonas aeruginosa; Pyruvate; Regulation; Resistance; Resolution; Respiratory Chain; Role; Signal Transduction; Site; Source; Standardization; Structure; Suspensions; Techniques; Testing; Virulence; Work; antimicrobial drug; appendage; base; cell community; cystic fibrosis patients; defined contribution; dimer; electron donor; feeding; genetic approach; genetic regulatory protein; in vivo; innovation; insight; microbial community; pathogen; response; therapeutic target

Although a diverse arsenal of antimicrobial drugs has been developed, bacterial and fungal infections remain prevalent worldwide. The formation of multicellular communities of microbes, called biofilms, is a common feature of these diseases that contributes to their endurance. Cells in biofilms are held together by an extracellular matrix and differ from those grown in liquid cultures with respect to their metabolism and sensitivity to antimicrobial drugs. Our long-term goal is to define the integrated, redox-based regulatory networks and metabolisms that support survival of bacteria in biofilms, with a focus on the pathogen Pseudomonas aeruginosa. We hypothesize that the changing redox states of cells in developing biofilms affect multicellular behavior, virulence, and susceptibility to antibiotics. A standardized colony biofilm morphology assay facilitates our investigation of mechanisms that underpin biofilm-specific metabolism and feature formation. We will use basic molecular approaches combined with newly developed and innovative techniques, including electrochemical and microscopic analysis of biofilms at the micron scale, to address fundamental questions regarding the use of redox-active substrates for metabolism and the global regulation of biofilm matrix in response to redox cues: (1) How does P. aeruginosa balance its cellular redox state in the oxygen- limited regions of biofilms? (2) How does redox control of cellular signaling determine overall community morphology and cellular arrangement within the biofilm? (3) How does the use of pyruvate and lactate, important energy sources and metabolic intermediates, contribute to survival in biofilms and metabolism during host infection? As P. aeruginosa is a major cause of infections in hospitals and in patients with cystic fibrosis, we are motivated by the potential for these mechanisms to serve as therapeutic targets.

尽管已经开发了多种抗菌药物，但细菌和真菌感染仍然存在。 在世界范围内流行。微生物的多细胞群落的形成，称为生物膜，是一种常见的 这些疾病的特点，有助于他们的耐力。生物膜中的细胞通过一种 细胞外基质，并且在它们的代谢方面不同于在液体培养物中生长的那些， 对抗菌药物敏感。我们的长期目标是定义集成的、基于氧化还原的调节 支持细菌在生物膜中生存的网络和代谢，重点是病原体 绿脓杆菌。我们假设，细胞在发育生物膜中的氧化还原状态的变化影响了 多细胞行为、毒力和对抗生素的敏感性。标准化菌落生物膜形态 分析有助于我们研究生物膜特异性代谢和特征的机制 阵我们将使用基本的分子方法结合新开发的和创新的技术， 包括微米级生物膜的电化学和显微镜分析，以解决基本的 关于使用氧化还原活性底物进行代谢和生物膜的全球调节的问题 矩阵对氧化还原线索的反应：（1）铜绿假单胞菌如何平衡其在氧气中的细胞氧化还原状态- 有限的生物膜区域？(2)细胞信号的氧化还原控制如何决定整个群落 生物膜内的形态和细胞排列？(3)如何利用丙酮酸和乳酸， 重要的能量来源和代谢中间体，有助于生物膜中的存活和代谢， 宿主感染？由于铜绿假单胞菌是医院和囊性纤维化患者感染的主要原因， 我们的动机是这些机制作为治疗靶点的潜力。