The role of metal ion homeostasis in regulating bacterial capsule production

金属离子稳态在调节细菌荚膜产生中的作用

• 批准号: 10360103
• 负责人: Julia E. Martin
• 金额: $ 40.85万
• 依托单位: IDAHO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360103
• 关键词: Affect; Anabolism; Antibiotic Therapy; Award; Bacteria; Bacterial Adhesins; Bacterial Antibiotic Resistance; Bacterial Capsules; Bacterial Infections; Biochemical; Biogenesis; Biology; Biomedical Research; Calcium; Career Choice; Cell physiology; Chemistry; Child; Clinical Treatment; Communicable Diseases; Dangerousness; Data; Development; Disease; Disease Progression; Elderly; Environment; Environmental Risk Factor; Enzymes; Exhibits; Exposure to; Foundations; Future; Goals; Growth; Homeostasis; Human; Idaho; Immune; Impairment; Infection; Interdisciplinary Study; Intervention; Ions; Knowledge; Laboratories; Literature; Manganese; Membrane Proteins; Metals; Microbiological Techniques; Micronutrients; Mission; Modeling; Modernization; Molecular; Multi-Drug Resistance; National Institute of Allergy and Infectious Disease; Nutrient; Outcome; Oxygen; Pathogenesis; Pathogenicity; Pathway interactions; Physiological; Play; Polysaccharides; Population; Positioning Attribute; Production; Proteins; Proteomics; Public Health; RNA; Research; Research Technics; Role; Signal Transduction; Streptococcus pneumoniae; Surface Antigens; Talents; Therapeutic; Thick; Transition Elements; United States National Institutes of Health; Universities; Up-Regulation; Virulence; Virulence Factors; Zinc; antimicrobial; arm; base; calcium supplementation; cofactor; combat; design; drug development; effective therapy; enzyme activity; experience; graduate student; innovation; interest; novel; novel therapeutics; pathogen; pathogenic bacteria; prevent; programs; response; transcriptome sequencing; undergraduate student

Project Summary/Abstract Capsular polysaccharide (CPS) produced by pathogenic bacteria is a key virulence determinant for bacterial survival in the human host, but knowledge of how CPS production is regulated remains limited. Given the need for pathogenic bacteria to modulate CPS expression (thickness) among various host niches during disease progression, we postulate here that available environmental factors such as metal ion micronutrients can influence CPS production. The long-term goal is to help develop alternative metal-based antimicrobial therapeutics for clinical treatment of bacterial diseases in humans. The overall objectives in this application, which constitute the first step toward attainment of the long-term goal, are to identify the molecular mechanisms by which cellular metal ion ratios, specifically manganese (Mn), zinc (Zn), and calcium (Ca), influence CPS production, while increasing exposure of undergraduates to research and enhancing Idaho State University’s biomedical research enterprise. The central hypothesis is that metal ion micronutrients regulate CPS biogenesis via direct modulation of enzyme activity in pathogenic bacteria using Streptococcus pneumoniae (Spn) as a Gram-positive model bacterium. The rationale for this project is that a mechanistic understanding of how cellular metal ion ratios regulate CPS expression levels would provide new opportunities for the subsequent identification and development of targets for the design of novel interventions to treat human pathogenic bacterial infections. To attain the overall objectives, we will pursue the following specific aims: 1) Identify the mechanism(s) whereby bioavailable Mn/Zn ratios affect CPS production; and 2) Determine the role of Ca in Mn homeostasis and CPS biogenesis. The first aim will assess the physiological and biochemical impact of bioavailable Mn/Zn ratios on several Mn-utilizing enzymes involved in various arms of the Spn CPS biosynthetic pathway. The second aim will assess the impact of Ca/Mn ratios on the intracellular metal landscape and CPS biosynthesis in coordination with RNAseq and proteomic analysis. The overall approach combines classical microbiology techniques with modern day applications that span the interface of biology and chemistry, thereby exposing undergraduates to interdisciplinary research techniques. The research proposed in this application is innovative, in the applicant’s opinion, because it represents a substantive departure from the status quo by focusing on the impact of overall cellular metal ion micronutrient ratios and their capacity to regulate bacterial CPS biogenesis. The research proposed will also further the understanding of how cellular metal ion availability serve as signaling factors that influence global cellular changes and cellular programing during pathogenesis. The proposed research is significant because it is expected to provide a strong foundation for subsequent future design of mechanistic and alternative metal- based drug development strategies to combat human bacterial pathogens prone to exhibiting multidrug resistance.

项目总结/摘要 由病原菌产生的荚膜多糖（CPS）是致病菌的关键毒力决定因子， 细菌在人类宿主中的生存，但对CPS产生如何调节的了解仍然有限。给定 病原菌需要在不同宿主小生境中调节CPS表达（厚度）， 疾病进展，我们在这里假设，可用的环境因素，如金属离子微量营养素， 会影响CPS的生产长期目标是帮助开发替代金属基抗菌剂 用于临床治疗人类细菌性疾病的治疗剂。本申请的总体目标是， 这是实现长期目标的第一步， 细胞金属离子比率，特别是锰（Mn）、锌（Zn）和钙（Ca）， 影响CPS生产，同时增加本科生对研究的接触，提高爱达荷州 州立大学的生物医学研究企业。核心假设是金属离子微量营养素 使用链球菌通过直接调节病原菌中的酶活性来调节CPS生物发生 肺炎链球菌（Spn）作为革兰氏阳性模式细菌。这个项目的基本原理是， 了解细胞金属离子比例如何调节CPS表达水平将提供新的机会 用于随后识别和开发新干预措施的目标，以治疗 人类病原性细菌感染。为达致整体目标，我们会从以下几个方面， 目的：1）确定生物可利用的Mn/Zn比例影响CPS生产的机制; 2）确定 钙在锰稳态和CPS生物合成中的作用。第一个目标将评估生理和 生物可利用的锰/锌比对参与细胞各分支的几种利用锰的酶的生化影响 Spn CPS生物合成途径。第二个目的是评估Ca/Mn比对细胞内钙离子浓度的影响。 金属景观和CPS生物合成与RNAseq和蛋白质组学分析协调。整体 这种方法将经典的微生物学技术与现代应用相结合， 生物学和化学，从而使本科生接触到跨学科的研究技术。的 本申请中提出的研究是创新的，在申请人看来，因为它代表了一个 实质性地脱离现状，侧重于整体细胞金属离子微量营养素的影响 比率和它们调节细菌CPS生物合成的能力。拟议的研究还将进一步促进 了解细胞金属离子的可用性如何作为影响全球细胞的信号因素， 发病过程中的变化和细胞编程。这项研究之所以重要，是因为 预计将为后续的机械和替代金属的未来设计提供坚实的基础- 基于药物开发战略，以打击人类细菌病原体倾向于表现出多药 阻力