Innovative Strategies to Combat Antibiotic-resistant Infections

项目摘要/摘要： 对抗生素不再敏感的抗药性细菌感染是一种 迫在眉睫的灾难以及像最近的新冠肺炎危机一样，如果我们 都没有做好准备。这项建议利用基础科学发现来开发节省抗生素的药物 对大多数病原体的治疗有影响的药物被疾控中心指定为对人类健康的威胁。 项目1和项目2针对表达粘附性菌毛的多重耐药(MDR)革兰氏阴性病原体 在急性和慢性/复发性尿路的宿主生境中定居和感染所必需的 感染(UTI)和导管相关性UTI(CAUTI)，包括耐多药不动杆菌、碳青霉烯耐药 肠杆菌科(Cre)和产超广谱β-内酰胺酶(ESBL)的肠杆菌科。 项目2对这一清单进行了扩展，以包括其他令人关注的革兰氏阴性病原体。由于尿路感染占 约10%的抗生素在人类使用，节省抗生素的疗法的发展不仅将使 治疗耐药感染，但通过减少目前抗生素的使用，将减少选择性 抵抗的压力。项目1的重点是使用糖仿制技术中和细菌菌毛粘附素 在核心1中设计和在核心2中开发的单抗将阻止细菌之间的关键相互作用 粘附素及其宿主配体。糖仿制技术在中和伴侣/引座者方面显示出巨大的前景 体内粘附素治疗疾病的途径(CUP)。例如，甘露糖苷可以中和致尿路感染的E. Coli(UPEC)粘附素FimH是治疗和预防尿路感染的有效疗法，因为FimH是 UPEC来定植膀胱。与葛兰素史克合作，已经选择了一种甘露糖苷来 进入1a/1b期临床试验，从而验证这一策略的潜力。治疗性单抗有 尚未被完全利用来治疗传染病的。随着抗生素耐药性的上升，是时候 应用这一策略。项目1还将以革兰氏阳性肠球菌的分类酶组装的粘附素为目标， 这会导致CAUTIs，通常是MDR。项目2将使用类似的工具来专注于 将项目1中的革兰氏阴性粘附素组装在菌毛纤维的顶端。项目3将面向所有Gram- 疾病预防控制中心通过进一步开发转基因杀虫剂，将阳性物种确定为重大威胁， 一种新的环稠合2-吡啶酮化合物家族，对广谱的革兰氏杆菌有杀菌作用。 阳性物种。这些核心将与科学项目完全结合，提供计算和 合成药物化学在小分子治疗学发展中的应用(CORE 1) 针对细菌蛋白的高通量单抗的产生(核心2)。结合了知识、专业知识 项目和核心项目负责人的成功将导致抗生素节约的发展 治疗越来越多的抗生素耐药病原体，以延缓复发 抗生素时代之前，常见的感染基本上是无法治愈的。

PROJECT SUMMARY/ ABSTRACT: Antibiotic-resistant bacterial infections that are no longer sensitive to our life saving antibiotic arsenal are a looming catastrophe and like the recent COVID-19 crisis, will have dire consequences for human health if we are not prepared. This proposal leverages basic science findings for development of antibiotic-sparing medicines with impact on treatment for most pathogens designated threats to human health by the CDC. Projects 1 and 2 target multi-drug resistant (MDR) Gram-negative pathogens that express adhesive pili required for colonization and infection in the host habitats involved in acute and chronic/recurrent urinary tract infections (UTIs) and catheter-associated UTIs (CAUTIs), including MDR Acinetobacter, carbapenem-resistant Enterobacteriaceae (CRE) and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. Project 2 expands on this list to include other Gram-negative pathogens of concern. Since UTIs account for ~10% of antibiotic use in humans, the development of antibiotic-sparing therapeutics will not only allow treatment of antibiotic-resistant infections, but by reducing the use of current antibiotics, will decrease selective pressures for resistance. Project 1 is focused on neutralizing bacterial pilus adhesins using glycomimetics designed in CORE 1 and mAbs developed in CORE 2 that will block critical interactions between bacterial adhesins and their host ligands. Glycomimetics have shown great promise in neutralizing chaperone/usher pathway (CUP) adhesins in vivo to treat disease. For example, mannosides, which neutralize uropathogenic E. coli (UPEC) adhesin FimH, are potent therapeutics for treating and preventing UTI, since FimH is required by UPEC to colonize the bladder. In collaboration with GlaxoSmithKline a mannoside has been selected to proceed into Phase 1a/1b clinical trials, thus validating the potential of this strategy. Therapeutic mAbs have not yet been fully harnessed for treating infectious diseases. With antibiotic resistance on the rise, it is time to apply this strategy. Project 1 will also target a sortase-assembled pilus adhesin of Gram-positive enterococci, which causes CAUTIs and is often MDR. Project 2 will use similar tools to focus on the CUP machinery that assembles the Gram-negative adhesins in Project 1 at the tip of pilus fibers. Project 3 will target all Gram- positive species identified by the CDC as significant threats by furthering the development of GmPcides, a novel family of ring-fused 2-pyridone compounds that are bactericidal against a broad spectrum of Gram- positive species. The COREs will be fully integrated with the Scientific Projects providing computational and synthetic medicinal chemistry in the development of small molecule therapeutics (CORE 1) and the application of high throughput mAb generation against bacterial proteins (CORE 2). The combined knowledge, expertise and successes of the Leaders of the Projects and Cores will lead to the development of antibiotic-sparing therapeutics for treatment of the growing number of antibiotic-resistant pathogens to stave off the return to the pre-antibiotic era when common infections were essentially untreatable.