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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

基本信息

批准号：
10391571
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
项目类别：
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/10391571
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 opportunistic pathogen pathogen response therapeutic target

项目摘要

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.

尽管已经开发了各种各样的抗微生物药物，但细菌和真菌感染仍然存在流行于世界各地。微生物多细胞群落的形成，称为生物膜，是一种常见的这些疾病的特征有助于他们的耐力。生物膜中的细胞由一个细胞外基质，不同于液体培养的细胞，其代谢和对抗菌药物的敏感性。我们的长期目标是定义以氧化还原为基础的综合监管支持细菌在生物膜中生存的网络和代谢，重点是病原体铜绿假单胞菌。我们假设发育中的生物膜中细胞氧化还原状态的变化会影响多细胞行为、毒性和对抗生素的敏感性。一种标准化的菌落生物膜形态化验有助于我们研究支持生物膜特定代谢和特征的机制队形。我们将使用基本的分子方法与新开发和创新的技术相结合，包括微米级生物膜的电化学和显微分析，以解决基本问题关于使用氧化还原活性底物进行代谢和生物被膜的全球调节的问题基质对氧化还原信号的反应：(1)铜绿假单胞菌是如何在氧气中平衡其细胞氧化还原状态的？生物膜的有限区域？(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)丙酮酸和乳酸的利用如何，重要的能源和代谢中间体，有助于在生物膜中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。

项目成果

期刊论文数量（38）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Motility, Chemotaxis and Aerotaxis Contribute to Competitiveness during Bacterial Pellicle Biofilm Development.

DOI：
10.1016/j.jmb.2015.06.014
发表时间：
2015-11-20
期刊：
Journal of molecular biology
影响因子：
5.6
作者：
Hölscher T;Bartels B;Lin YC;Gallegos-Monterrosa R;Price-Whelan A;Kolter R;Dietrich LEP;Kovács ÁT
通讯作者：
Kovács ÁT

Gradients and consequences of heterogeneity in biofilms.

DOI：
10.1038/s41579-022-00692-2
发表时间：
2022-10
期刊：
Nature reviews. Microbiology
影响因子：
0
作者：
通讯作者：

Redox cycling-based detection of phenazine metabolites secreted from Pseudomonas aeruginosa in nanopore electrode arrays.

DOI：
10.1039/d0an02022b
发表时间：
2021-02-21
期刊：
The Analyst
影响因子：
0
作者：
Do H ;Kwon SR ;Baek S ;Madukoma CS ;Smiley MK ;Dietrich LE ;Shrout JD ;Bohn PW
通讯作者：
Bohn PW

The Pseudomonas aeruginosa Complement of Lactate Dehydrogenases Enables Use of d- and l-Lactate and Metabolic Cross-Feeding.