Transition Metal Homeostasis and Reactive Sulfur Species in Bacterial Pathogens

细菌病原体中的过渡金属稳态和活性硫物种

• 批准号: 10625271
• 负责人: DAVID P. GIEDROC
• 金额: $ 45.43万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625271
• 关键词: Acinetobacter baumannii; Analytical Chemistry; Anti-Bacterial Agents; Antibiotics; Antioxidants; Area; Bacteria; Biogenesis; Bioinorganic Chemistry; Biological Process; Cells; Communicable Diseases; Consensus; Development; Drug Metabolic Detoxication; Genetic Transcription; Health; Homeostasis; Human; Hydrogen Sulfide; Infection; Inorganic Chemistry; Iron; Kinetics; Knowledge; Life; Link; Mass Spectrum Analysis; Mediating; Methods; Microbial Physiology; Modification; Multidrug-resistant Acinetobacter; Nosocomial Infections; Nutrient; Nutritional Immunity; Organism; Oxygen; Pathway interactions; Positioning Attribute; Process; Proteins; Proteomics; Reactive Nitrogen Species; Relaxation; Repressor Proteins; Research; Signal Transduction; Signaling Molecule; Species Specificity; Staphylococcus aureus; Starvation; Streptococcus pneumoniae; Sulfur; Transcription Repressor; Transcriptional Regulation; Transition Elements; Zinc; antimicrobial; biophysical chemistry; design; experimental study; human pathogen; innovation; interdisciplinary approach; interest; metal poisoning; novel; pathogen; pathogenic bacteria; programs; respiratory pathogen; sensor; weapons

ABSTRACT Bacterial infectious disease is a global threat to human health and there is an urgent need to develop new antimicrobials that limit the impact of life-threatening pathogens. These pathogens include the major causative agents of nosocomial infections, e.g., Acinetobacter baumannii and Staphylococcus aureus, and a major respiratory pathogen, Streptococcus pneumoniae. In this renewal application, we seek continuation of our innovative, strongly integrated and topical research program positioned at an intersection of inorganic chemistry and microbial physiology, designed to tackle significant gaps in our knowledge in bacterial transition metal homeostasis (metallostasis) and hydrogen sulfide homeostasis. My group has long-standing interests in the transcriptional repressor proteins (metallosensors) and metallochaperones that allow a bacterium to respond to host efforts to restrict transition metal availability or induce metal toxicity. Our subsequent discovery of transcriptional regulators that “sense” downstream more oxidized forms of hydrogen sulfide, collectively termed reactive sulfur species (RSS), is foundational to our understanding of hydrogen sulfide signaling via protein persulfidation (S-sulfuration). Indeed, an emerging consensus holds that the biogenesis of hydrogen sulfide and RSS provides protection against host weapons reactive oxygen and reactive nitrogen species, and antibiotics, where they function as antioxidants and signaling molecules. Future research will be carried out in four general areas: 1) Investigating allostery in transcriptional regulation, where we extend our comprehensive physical description of metallosensors as dynamically-anchored “allosteric inorganic switches” to RSS sensors, using state-of-the-art methyl-specific NMR relaxation experiments and a novel mass spectrometry-based kinetic profiling method used to elucidate the broad principles of RSS specificity in diverse structural classes of regulators; 2) critically evaluate the RSS signaling hypothesis in A. baumannii, which posits that persulfidation is a regulatory modification, completely unexplored in bacteria; 3) deduce the global impact of host transition metal (zinc, iron) starvation (nutritional immunity) using complementary proteomics and metalloproteomics workflows to define changes in the metalloproteome while identifying metallochaperone targets, in A. baumannii; and 4) elucidate a poorly understood, infection-relevant iron-catecholate acquisition and detoxification pathway in S. pneumoniae. Our multidisciplinary approach, which seamlessly spans biophysical, bioinorganic and analytical chemistries to microbial physiology, will transform our understanding of foundational principles of pathogen metallostasis and hydrogen sulfide/RSS biogenesis in an effort to discover and characterize new players and biological processes that can be targeted by novel antibacterial strategies.

摘要 细菌性传染病是一种全球性的威胁人类健康的疾病，迫切需要开发新的 限制威胁生命的病原体的影响的抗菌剂。这些病原体包括主要的致病性 医院感染的病原体，例如，鲍曼不动杆菌和金黄色葡萄球菌，以及主要的 呼吸道病原体，肺炎链球菌。在这一更新申请中，我们寻求继续我们的 创新，强集成和专题研究计划定位在无机化学的交叉点 和微生物生理学，旨在解决我们在细菌过渡金属方面的知识空白 稳态（金属稳态）和硫化氢稳态。我的组织长期以来对 转录抑制蛋白（金属传感器）和金属伴侣，允许细菌响应 宿主努力限制过渡金属的可用性或诱导金属毒性。我们后来发现 转录调节因子“感应”下游更多氧化形式的硫化氢，统称为 反应性硫物质（RSS）是我们了解蛋白质介导的硫化氢信号传导的基础 过硫化（S-硫化）。事实上，一个正在形成的共识认为，硫化氢的生物成因和 RSS提供对宿主武器活性氧和活性氮物质以及抗生素的保护， 在那里它们起到抗氧化剂和信号分子的作用。未来的研究将在四个方面展开。 领域：1）研究转录调控中的变构，在那里我们扩展了我们全面的物理 作为RSS传感器的动态锚定“变构无机开关”的金属传感器的描述， 最先进的甲基特异性NMR弛豫实验和一种新的基于质谱的动力学 分析方法用于阐明RSS特异性在不同结构类别的广泛原则， 2）对A.鲍曼不动杆菌，它假定过硫化是 一种调节性修饰，在细菌中完全未被探索; 3）推断宿主过渡金属的全球影响 (zinc铁）饥饿（营养免疫）使用互补蛋白质组学和金属蛋白质组学工作流程 为了确定金属蛋白质组的变化，同时确定金属伴侣蛋白靶点，在A.鲍曼不动杆菌;以及4） 阐明一个知之甚少，感染相关的铁儿茶酚收购和解毒途径，在S。 肺炎。我们的多学科方法，无缝跨越生物物理，生物无机和分析 从化学到微生物生理学，将改变我们对病原体基本原理的理解 成矿作用和硫化氢/RSS生物成因，努力发现和表征新的球员， 可以通过新的抗菌策略靶向的生物过程。

项目成果

Staphylococcus aureus sqr Encodes a Type II Sulfide:Quinone Oxidoreductase and Impacts Reactive Sulfur Speciation in Cells.

• DOI: 10.1021/acs.biochem.6b00714
• 发表时间: 2016-11-29
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Shen J;Peng H;Zhang Y;Trinidad JC;Giedroc DP
• 通讯作者: Giedroc DP

Protocol for using organic persulfides to measure the chemical reactivity of persulfide sensors.

• DOI: 10.1016/j.xpro.2022.101424
• 发表时间: 2022-06-17
• 期刊: STAR protocols

Increased intracellular persulfide levels attenuate HlyU-mediated hemolysin transcriptional activation in Vibrio cholerae.

• DOI: 10.1016/j.jbc.2023.105147
• 发表时间: 2023-09
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Diez, Cristian M. Pis;Antelo, Giuliano T.;Dalia, Triana N.;Dalia, Ankur B.;Giedroc, David P.;Capdevila, Daiana A.
• 通讯作者: Capdevila, Daiana A.

Metabolic and Structural Insights into Hydrogen Sulfide Mis-Regulation in Enterococcus faecalis.

• DOI: 10.3390/antiox11081607
• 发表时间: 2022-08-19
• 期刊: Antioxidants (Basel, Switzerland)

A Mn-sensing riboswitch activates expression of a Mn2+/Ca2+ ATPase transporter in Streptococcus.

Mn 感应核糖开关可激活链球菌中 Mn2/Ca2 ATP 酶转运蛋白的表达。

• DOI: 10.1093/nar/gkz494
• 发表时间: 2019
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Martin,JuliaE;Le,MyT;Bhattarai,Nabin;Capdevila,DaianaA;Shen,Jiangchuan;Winkler,MalcolmE;Giedroc,DavidP
• 通讯作者: Giedroc,DavidP