Structural and functional studies of YbtPQ for fighting bacterial infections

YbtPQ 对抗细菌感染的结构和功能研究

• 批准号: 10644889
• 负责人: Hongjin Zheng
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-17 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644889
• 关键词: ATP-Binding Cassette Transporters; Accounting; Address; Adopted; Anti-Bacterial Agents; Antibiotic Resistance; Back; Bacteria; Bacterial Infections; Binding; Biochemistry; Biology; Biophysics; Cell membrane; Clinical; Cryoelectron Microscopy; Data; Development; Drug Delivery Systems; Future; Goals; Growth; Health; Human; Infection; Ions; Knowledge; Maps; Mediating; Membrane; Membrane Transport Proteins; Metals; Microbiology; Micronutrients; Mission; Modeling; Molecular; Molecular Conformation; Movement; Nutritional; Nutritional Immunity; Pathogenicity; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Process; Protein Conformation; Proteins; Public Health; Resolution; Scheme; Side; Siderophores; Solvents; Structure; Structure-Activity Relationship; Theft; Therapeutic; Time; Transmembrane Domain; United States; United States National Institutes of Health; Urinary tract infection; Uropathogenic E. coli; Virulence; War; Woman; chelation; design; drug development; fascinate; fighting; high throughput screening; inhibitor; innovation; interdisciplinary approach; interest; novel; particle; pathogen; small molecule; small molecule inhibitor; societal costs; structural biology; translational impact; uptake; yersiniabactin

One of the eternal wars between the host and pathogens is the fight for nutritional metal ions. Bacteria have evolved multiple pathways to achieve that, including the one mediated by a group of small molecules called siderophores that are often critical for the virulence of the bacteria. The long-term goal is to help develop potential molecules targeting the siderophore-mediated metal uptake process, so to treat bacterial infections. However, one of the critical steps in this process, the substrate uptake mediated by ATP-binding-cassette (ABC) importers, is poorly understood. The overall objective in this proposal is to address the problem by studying the detailed molecular mechanism of a specific siderophore ABC importer from uropathogenic Escherichia coli (UPEC): the yersiniabactin (Ybt) importer YbtPQ. The rational is that, with detailed knowledge gained here, it will be possible to design and optimize small molecules to specifically target YbtPQ. To accomplish the goal, two specific aims will be pursued: 1) reconstructing its complete transport cycle by structural studies; and 2) investigating its substrate selectivity and interaction with potential inhibitors. The multidisciplinary approach used here include structural biology, biochemistry, biophysics, as well as microbiology. The proposal is innovative because 1) YbtPQ is an exporter-like importer, representing a substantial departure from the established paradigm of ABC importers; and 2) the results will provide potential inhibitors against YbtPQ that could be clinically useful in the future. Last but not least, this study is also significant because it is expected to not only reveal novel molecular mechanism of exporter-like importer, but also provide scientific justification for further development of drugs against siderophore ABC importers.

宿主和病原体之间的永恒战争之一是为营养金属离子而战。细菌有 进化了多个途径以实现这一目标，包括由一组称为的小分子介导的途径 铁载体通常对于细菌的毒力至关重要。长期目标是帮助发展潜力 靶向铁载体介导的金属摄取过程的分子，以治疗细菌感染。然而， 在此过程中的关键步骤之一，是由ATP结合件（ABC）进口商介导的底物摄取， 理解很差。该提案的总体目的是通过研究详细信息来解决该问题 来自尿液疾病大肠杆菌（UPEC）的特定铁载体ABC进口剂的分子机制： Yersiniabactin（YBT）进口商YBTPQ。理性是，随着这里获得的详细知识，将有可能 设计和优化小分子以特别针对YBTPQ。为了实现目标，两个具体的目标 将追求：1）通过结构研究重建其完整的运输周期； 2）调查其 底物选择性和与潜在抑制剂的相互作用。这里使用的多学科方法包括 结构生物学，生物化学，生物物理学以及微生物学。该提议具有创新性，因为1） YBTPQ是一个像出口商一样的进口商 进口商； 2）结果将提供对YBTPQ的潜在抑制剂，这在临床上可能在临床上有用 未来。最后但并非最不重要的一点是，这项研究也很重要，因为它不仅可以揭示新的分子 出口商样进口商的机制，但也为进一步开发药物提供了科学理由 反对铁载体ABC进口商。