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

项目概要/摘要：当前的COVID-19大流行直接向我们展示了 对潜在的健康危机毫无准备可能带来的后果，并提醒社会， 传染病对整个人类健康和社会仍可能造成的灾难性影响。的 抗药性细菌病原体的出现和迅速传播， 这是一场危机，对人类整体健康的威胁日益严重。U19旨在应对这一日益严重的危机 通过产生和开发特异性靶向于 致病菌的主要毒力机制。CORE 1将完全集成， 科学项目提供计算和合成药物化学的设计，创造和 表征将靶向常见细菌毒力机制的小分子治疗剂， 治疗感染病原体的可行性，无论病原体的抗生素敏感性概况如何。 在项目1中，该CORE将产生基于小分子糖苷的细菌粘附素凝集素结构域 拮抗剂对E.大肠杆菌、克雷伯菌属、不动杆菌属和肠球菌属引起尿路感染 感染（UTI）和导管相关UTI。这项工作是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。这个团队已经成功地开发了 合理设计的糖苷。值得注意的是，一种被称为甘露糖苷的候选FimH拮抗剂，由 核心领导人Janetka博士已被批准用于人体1a/1b期临床试验。这是一个明确 验证本提案中的方法。在项目2中，我们将针对 无处不在的伴侣引导途径（CUP）系统，其中有各种各样的革兰氏阴性细菌， 包括本RFA感兴趣的那些，用于在其表面上精心制作粘附菌毛，以介导不同的 与特定宿主表面和组织结合。被称为杀菌剂的环稠合的2-吡啶酮已经被用于制备杀菌剂。 开发了作为分子伴侣CUP系统的肽模拟物抑制剂。我们将扩展这些 研究靶向外膜组装蛋白，引导，以阻止其功能，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- 吡啶酮基化合物，命名为GmPcides（革兰氏阳性杀菌剂），我们发现它具有杀菌作用 针对引起医疗保健相关感染的各种革兰氏阳性病原体。核心领导 博士Almqvist在设计和优化这些化合物方面的专业知识将是成功的关键 完成项目2（杀菌剂）和项目3（除草剂）。核心领导人Janetka博士和Almqvist博士 在合成有机化学以及合理设计和合成治疗药物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有力的化学支持， 药物发现领导本U19提案的所有3个项目。

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.