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

项目摘要/摘要：当前的新冠肺炎疫情向我们展示了第一手的可怕 对潜在的健康危机毫无准备可能带来的后果，并提醒社会作为一个 传染病仍然可能对整个人类健康和社会产生灾难性的影响。这个 耐药细菌病原体的出现和迅速传播构成了一个严重迫在眉睫的全球 危机和对整个人类健康的日益严重的威胁。这款U19旨在对抗这场日益严重的危机 通过产生和开发针对特定目标的节省抗生素的疗法 病原菌使用的关键毒力机制。核心1将完全集成，与每个 提供计算和合成药物化学的科学项目的设计、创造和 针对常见细菌毒力机制的小分子疗法的特征 治疗感染病原体的可行性，而不考虑病原体的抗生素敏感性特征。 在项目1中，这个核心将产生基于小分子糖苷的细菌粘附素凝集素结构域 对大肠埃希菌、克雷伯氏菌、不动杆菌和肠球菌引起尿路的关键拮抗剂 感染(尿路感染)和导管相关性尿路感染。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及其生物学功能。这个团队已经成功地开发出 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 核心领导者Janetka博士已获准在人类进行1a/1b期临床试验。这是一个明确的 对本提案中的方法进行验证。在项目2中，我们将针对 无处不在的伴侣引导途径(CUP)系统，它是一种广泛的革兰氏阴性细菌， 包括RFA感兴趣的那些，用来在它们的表面上精心制作粘附毛，以调解不同的 结合到特定的宿主表面和组织。被称为杀菌剂的环稠合2-吡啶酮已经被 开发了作为伴侣杯系统的模拟肽抑制剂的药物。我们将在这些方面进行扩展 研究靶向外膜组装蛋白，引座者，以阻断其功能，增加 外膜对其他抗生素的渗透性。在项目3中，我们寻求扩大我们的收集2- 以吡啶酮为基础的化合物，被称为GmP(革兰氏阳性杀菌剂)，我们已经发现它们具有杀菌作用 对抗导致医疗保健相关感染的各种革兰氏阳性病原体。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将是成功 完成项目2(杀菌剂)和项目3(转基因杀虫剂)。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。 这两个小组的知识和过去的成功结合在一起，将提供强有力的化学支持和 领导该U19提案的所有3个项目的药物发现。

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.