Innovative Strategies to Combat Antibiotic-resistant Infections

项目总结/摘要： 抗生素耐药性细菌感染，不再敏感，我们的救生抗生素阿森纳是一个 迫在眉睫的灾难，就像最近的COVID-19危机，将对人类健康造成可怕的后果，如果我们 没有准备好。该提案利用基础科学发现来开发节约农药的方法， 对疾病预防控制中心指定的威胁人类健康的大多数病原体的治疗有影响的药物。 项目1和2针对表达粘附性皮利的多药耐药革兰氏阴性病原体 急性和慢性/复发性尿路感染所涉及的宿主栖息地中的定殖和感染所需 感染（UTI）和导管相关UTI（UTI），包括MDR不动杆菌、碳青霉烯类耐药 肠杆菌科（CRE）和产超广谱β-内酰胺酶（ESBL）肠杆菌科。 项目2扩展了该列表，以包括其他革兰氏阴性病原体。由于尿路感染占 约10%的抗生素用于人类，开发抗生素保留疗法不仅可以 抗生素耐药感染的治疗，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的重点是使用糖模拟物中和细菌菌毛粘附素 CORE 1中设计的mAb和CORE 2中开发的mAb将阻断细菌之间的关键相互作用 粘附素及其宿主配体。糖模拟物在中和分子伴侣/引导剂方面显示出巨大的前景 途径（CUP）粘附素在体内治疗疾病。例如，甘露糖苷，其中和尿路致病性大肠杆菌。 大肠杆菌（UPEC）粘附素FimH是治疗和预防UTI的有效治疗剂，因为FimH是由UPEC粘附素所必需的。 UPEC在膀胱定植。在与葛兰素史克公司的合作中，选择了甘露糖苷， 进入1a/1b期临床试验，从而验证该策略的潜力。治疗性mAb具有 还没有完全用于治疗传染病。随着抗生素耐药性的上升，是时候 运用这一战略。项目1还将针对革兰氏阳性肠球菌的分选酶组装的菌毛粘附素， 这会导致急性胰腺炎，通常是耐多药项目2将使用类似的工具，重点放在CUP机器上， 将项目1中的革兰氏阴性粘附素组装在菌毛纤维的尖端。项目3将针对所有克- 通过进一步开发GmPcides，CDC将阳性物种确定为重大威胁， 一类新的环稠合2-吡啶酮化合物，其对广谱革兰氏菌具有杀菌作用， 阳性物种CORE将与科学项目完全集成，提供计算和 合成药物化学在小分子药物开发中的应用 针对细菌蛋白质的高通量mAb产生（CORE 2）。综合知识，专业知识 项目领导者和核心的成功将导致南极备件的发展 用于治疗越来越多的耐药性病原体以避免其返回 抗生素出现之前，普通感染基本上无法治疗。

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.