Rational design and synthesis of small molecule inhibitors targeting unique pathogenic mechanisms in Gram- and Gram+ bacteria important in UTI

针对尿道感染中重要的革兰氏菌和革兰氏菌独特致病机制的小分子抑制剂的合理设计和合成

• 批准号: 10577800
• 负责人: James W Janetka
• 金额: $ 68.05万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577800
• 关键词: 2-hydroxypyridine; Acinetobacter; Adhesives; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic susceptibility; Antibiotics; Area; Bacteria; Bacterial Adhesins; Bacterial Antibiotic Resistance; Binding; Binding Proteins; Biological Process; COVID-19 pandemic; Carbohydrates; Chemistry; Clinical Treatment; Clinical Trials; Collaborations; Collection; Communicable Diseases; Cytochrome P450; Dependence; Development; Discipline; Docking; Dose; Drug Kinetics; Enterococcus; Enzymes; Escherichia coli; Evaluation; Feces; Fibrinogen; Galactosides; Gastrointestinal tract structure; Generations; Glycosides; Gram-Negative Bacteria; Grant; Health; Heterocyclic Compounds; Human; Hydrogen Bonding; In Vitro; Individual; Infection; Intestines; Klebsiella; Knowledge; Leadership; Lectin; Ligands; Liquid substance; Mannose; Mannosides; Mediating; Membrane; Metabolic; Methodology; Molecular Chaperones; Molecular Conformation; Multi-Drug Resistance; Mus; Names; Organic Chemistry; Organic Synthesis; Pathogenesis; Pathogenicity; Pathway interactions; Peptides; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase Ia/Ib Clinical Trial; Pilum; Plasma; Plasma Proteins; Property; Proteins; Publishing; Pyridones; Rattus; Recurrence; Resistance development; Societies; Solubility; Structure; Surface; System; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Time; Tissues; Universities; Urinary tract infection; Uropathogen; Uropathogenic E. coli; Validation; Virulence; Washington; Work; analog; antagonist; antibiotic resistant infections; aqueous; bactericide; catheter associated UTI; clinical candidate; combat; design; drug discovery; drug resistant pathogen; galacturonic acid; global health; glycomimetics; healthcare-associated infections; improved; in silico; in vivo; inhibitor; innovation; interest; membrane assembly; microbial; molecular modeling; multi-drug resistant pathogen; novel therapeutics; pathogen; pathogenic bacteria; peptidomimetics; physical property; programs; rational design; scaffold; small molecule; small molecule inhibitor; small molecule therapeutics; structural biology; success

PROJECT SUMMARY/ABSTRACT: The current COVID-19 pandemic has shown us first-hand the dire consequences that being unprepared for potential health crises can bring, and has reminded society as a whole of the disastrous impact that infectious diseases can still have on overall human health and society. The emergence and rapid dissemination of antibiotic-resistant bacterial pathogens poses a severe looming global crisis and an increasingly dire threat to overall human health. This U19 seeks to combat this growing crisis through the generation and development of antibiotic-sparing therapeutics that are specifically targeted against key virulence mechanisms used by pathogenic bacteria. CORE 1 will be fully integrated, working with the each of the Scientific Projects providing computational and synthetic medicinal chemistry in the design, creation and characterization of small molecule therapeutics that will target common bacterial virulence mechanisms and viability to treat causative agents of infections, regardless of the pathogen's antibiotic susceptibility profiles. With Project 1, this CORE will produce small molecule glycoside-based bacterial adhesin lectin domain antagonists that are critical for E. coli, Klebsiellsa, Acinetobacter and Enterococcus to cause urinary tract infections (UTIs) and catheter-associated UTIs. This work is based on a deep understanding of the structures, ligands and biological functions of uropathogen adhesins. This team has already successfully developed rationally-designed glycosides. Notably, a candidate FimH antagonist called a mannoside, developed by CORE leader Dr. Janetka, has been approved for Phase 1a/1b clinical trials in humans. This is a clear validation of the approaches in this proposal. With Project 2, we will target the assembly machinery of the ubiquitous chaperone usher pathway (CUP) systems, which a wide variety of Gram-negative bacteria, including those of interest to this RFA, use to elaborate adhesive pilus on their surface to mediate distinct binding to particular host surfaces and tissues. Ring fused 2-pyridones called pilicides have already been developed that act as peptidomimetic inhibitors of the chaperone CUP system. We will expand on these studies to target the outer membrane assembly protein, the usher, to block its function and increase the permeability of the outer membrane to other antibiotics. With Project 3, we seek to expand our collection of 2- pyridone based compounds named GmPcides (Gram positive cides), which we have found are bactericidal against a wide variety of Gram-positive pathogens that cause healthcare associated infections. CORE leader Dr. Almqvist's expertise in designing and optimizing these compounds will be critical for the successful completion of projects 2 (pilicides) and 3 (GmPcides). Core leaders Dr. Janetka and Dr. Almqvist have extensive expertise in synthetic organic chemistry, and in the rational design and synthesis of therapeutics. The combined knowledge and past success from these two groups will provide strong chemistry support and drug discovery leadership to all 3 projects of this U19 proposal.

项目摘要/摘要：当前的 COVID-19 大流行让我们亲眼目睹了可怕的情况 对潜在的健康危机没有做好准备可能带来的后果，并提醒社会 传染病仍然可能对整个人类健康和社会造成的灾难性影响。这 抗生素耐药性细菌病原体的出现和快速传播给全球带来了迫在眉睫的严重威胁 危机以及对人类整体健康日益严峻的威胁。这支 U19 球队致力于应对这一日益严重的危机 通过产生和开发专门针对抗生素的抗生素节约疗法 病原菌使用的关键毒力机制。 CORE 1 将完全集成，与每个 的科学项目提供计算和合成药物化学的设计、创造和 针对常见细菌毒力机制的小分子疗法的表征 无论病原体的抗生素敏感性如何，都有治疗感染病原体的能力。 通过项目 1，该核心将生产基于小分子糖苷的细菌粘附素凝集素结构域 对大肠杆菌、克雷伯氏菌、不动杆菌和肠球菌引起尿路感染至关重要的拮抗剂 感染（尿路感染）和导管相关尿路感染。这项工作基于对结构的深刻理解， 尿路病原体粘附素的配体和生物学功能。该团队已经成功开发 合理设计的糖苷。值得注意的是，一种名为甘露糖苷的候选 FimH 拮抗剂，由 CORE 负责人 Janetka 博士已获准进行 1a/1b 期人体临床试验。这是一个明确的 验证本提案中的方法。在项目 2 中，我们的目标是装配机械 普遍存在的分子伴侣引导通路（CUP）系统，其中有多种革兰氏阴性细菌， 包括本 RFA 感兴趣的那些，用于在其表面上精心制作粘性菌毛以介导不同的 与特定宿主表面和组织结合。称为 pilicides 的环稠合 2-吡啶酮已经被 开发出作为伴侣 CUP 系统的拟肽抑制剂。我们将在这些方面展开 研究以外膜组装蛋白（引座蛋白）为目标，阻断其功能并增加 外膜对其他抗生素的渗透性。通过项目 3，我们寻求扩大我们的 2- 基于吡啶酮的化合物称为 GmPcides（革兰氏阳性菌），我们发现它具有杀菌作用 对抗多种导致医疗保健相关感染的革兰氏阳性病原体。核心领导者 Almqvist 博士在设计和优化这些化合物方面的专业知识对于成功至关重要 完成项目 2（pilicides）和 3（GmPcides）。核心领导者 Janetka 博士和 Almqvist 博士 在合成有机化学以及治疗药物的合理设计和合成方面拥有丰富的专业知识。 这两个小组的综合知识和过去的成功将提供强大的化学支持和 领导该 U19 提案的所有 3 个项目。