权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The molecular mechanism linking respiratory NADH oxidation and virulence in Staphylococcus aureus

金黄色葡萄球菌呼吸NADH氧化与毒力的分子机制

基本信息

批准号：
10170278
负责人：
ROBERT B GENNIS
金额：
$ 51.92万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
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：
2020-05-23 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10170278
关键词：
Aerobic Affect Anaerobic Bacteria Animals Bacteria Biochemical Biochemistry Bioenergetics Cell physiology Cells Cytochrome c Reductase Dangerousness Data Development Disease Elements Environment Enzymes Evolution Gene Expression Profiling Generations Genetic Genus staphylococcus Goals Growth Human body In Vitro Infection Kinetics Knock-out Knowledge Lead Link Longitudinal Studies Membrane Membrane Proteins Metabolic Metabolic Pathway Metabolism Methods Microbial Biofilms Molecular Monitor Morbidity - disease rate Multi-Drug Resistance NADH Nebraska Nitrates Organ Organism Oxidation-Reduction Oxygen Pathogenesis Pattern Process Production Proteins Proteomics Regulation Respiration Respiratory Chain Role Signal Transduction Signaling Molecule Site Staphylococcus aureus Staphylococcus aureus infection System Techniques Technology Testing United States Universities Variant Virulence Virulence Factors Vitamin K 2 alpha Toxin cost detection of nutrient differential expression flexibility interdisciplinary approach metabolomics microfluidic technology mortality new therapeutic target oxidation pathogen pathogenic bacteria promoter respiratory respiratory enzyme sensor histidine kinase therapeutically effective

项目摘要

ABSTRACT Staphylococcus aureus infections are a major cause of morbidity and mortality in the United States and across the globe. This is largely due to the evolution of multidrug-resistance and the ability of the bacterium to adapt its metabolism and bioenergetics to infect nearly every site of the human body. Thus, there is a significant need for the development of effective therapeutics against this organism. There are several critical gaps in our knowledge of how metabolic pathways used by S. aureus in different environments influence this pathogen virulence in vitro and inside the host. Therefore, our long-term goal is to elucidate how S. aureus receives signals from the environment in the host (e.g. oxygen concentration, nutrients), senses its own redox poise and energy status, and triggers metabolic changes, including the production of virulence factors. Our previous studies identified two respiratory enzymes in S. aureus called type 2 NADH dehydrogenases (NDH-2s: NdhC and NdhF) and revealed their importance for animal infection and organ colonization, and the production of virulence factors and biofilm formation in vitro. These results lead to our central hypothesis that the NADH-dependent respiratory chain is primarily responsible for controlling the NADH/NAD+ and MQH2/MQ (menaquinol/menaquinone) pools that are used by the cell to monitor its redox status and which we propose are major elements regulating virulence via specific global regulators. Guided by strong preliminary data, we propose to pursue three Specific Aims: (1) Determine the metabolic pathways utilized both in the presence and absence of each of the two NADH dehydrogenase enzymes, and the molecular mechanisms by which these enzymes modulate the production of α-toxin; (2) Determine why the presence of both NADH dehydrogenase enzymes is important for biofilm formation; (3) Determine if menaquinol is the signaling molecule that directly induces SrrB and SaeS autokinase activity in the SaeRS and SrrAB two-component systems, which are both critical for the regulation of virulence and biofilm formation. To accomplish these Aims, we have assembled a powerful team to employ a multidisciplinary approach that combines metabolomics, proteomics, genetics, microfluidics technology and biochemistry. Collectively, our proposed studies will have a broad impact on the field by uncovering the role of the respiratory chain in connecting environment signals with the intracellular redox poise that regulates S. aureus virulence. In the long term, these studies may reveal novel therapeutic targets to treat S. aureus-related diseases.

摘要