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:
- 金额:$ 51.92万
- 依托单位:
- 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:
- 关键词:AerobicAffectAnaerobic BacteriaAnimalsBacteriaBiochemicalBiochemistryBioenergeticsCell physiologyCellsCytochrome c ReductaseDangerousnessDataDevelopmentDiseaseElementsEnvironmentEnzymesEvolutionGene Expression ProfilingGenerationsGeneticGenus staphylococcusGoalsGrowthHuman bodyIn VitroInfectionKineticsKnock-outKnowledgeLeadLinkLongitudinal StudiesMembraneMembrane ProteinsMetabolicMetabolic PathwayMetabolismMethodsMicrobial BiofilmsMolecularMonitorMorbidity - disease rateMulti-Drug ResistanceNADHNebraskaNitratesOrganOrganismOxidation-ReductionOxygenPathogenesisPatternProcessProductionProteinsProteomicsRegulationRespirationRespiratory ChainRoleSignal TransductionSignaling MoleculeSiteStaphylococcus aureusStaphylococcus aureus infectionSystemTechniquesTechnologyTestingUnited StatesUniversitiesVariantVirulenceVirulence FactorsVitamin K 2alpha Toxincostdetection of nutrientdifferential expressionflexibilityinterdisciplinary approachmetabolomicsmicrofluidic technologymortalitynew therapeutic targetoxidationpathogenpathogenic bacteriapromoterrespiratoryrespiratory enzymesensor histidine kinasetherapeutically 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
项目成果
期刊论文数量(0)
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ROBERT B GENNIS其他文献
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{{ truncateString('ROBERT B GENNIS', 18)}}的其他基金
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
- 批准号:
10388212 - 财政年份:2020
- 资助金额:
$ 51.92万 - 项目类别:
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
- 批准号:
10611993 - 财政年份:2020
- 资助金额:
$ 51.92万 - 项目类别:
Using extreme thermophiles for the homologous expression of membrane proteins
使用极端嗜热菌进行膜蛋白的同源表达
- 批准号:
8027888 - 财政年份:2010
- 资助金额:
$ 51.92万 - 项目类别:
Using extreme thermophiles for the homologous expression of membrane proteins
使用极端嗜热菌进行膜蛋白的同源表达
- 批准号:
8318168 - 财政年份:2010
- 资助金额:
$ 51.92万 - 项目类别:
Using extreme thermophiles for the homologous expression of membrane proteins
使用极端嗜热菌进行膜蛋白的同源表达
- 批准号:
8515464 - 财政年份:2010
- 资助金额:
$ 51.92万 - 项目类别:
Using extreme thermophiles for the homologous expression of membrane proteins
使用极端嗜热菌进行膜蛋白的同源表达
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8150453 - 财政年份:2010
- 资助金额:
$ 51.92万 - 项目类别:
DEVELOPMENT OF MICROFLUIDIC DEVICE TO STUDY KINETICSOF HEME COPPER OXIDASES
开发用于研究血红素铜氧化酶动力学的微流体装置
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7181236 - 财政年份:2005
- 资助金额:
$ 51.92万 - 项目类别:
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