Innovative Strategies to Combat Antibiotic-resistant Infections

对抗抗生素耐药性感染的创新策略

基本信息

批准号：
10352464
负责人：
SCOTT J. HULTGREN
金额：
$ 216.51万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10352464
关键词：
2-hydroxypyridine Acinetobacter Acinetobacter baumannii Acute Address Adhesives Advanced Development Affect Affinity Animal Model Antibiotic Resistance Antibiotic Therapy Antibiotics Bacteria Bacterial Adhesins Bacterial Antibiotic Resistance Bacterial Infections Bacterial Proteins Basic Science Binding Bladder COVID-19 pandemic Catheters Cause of Death Cells Centers for Disease Control and Prevention (U.S.)Chemistry Chronic Clindamycin Clinical Treatment Clostridium difficile Collaborations Communicable Diseases Complex Crystallization Development Disease Drug resistance Enterobacteriaceae Enterococcus Erythromycin Escherichia coli Escherichia coli Adhesins Extended-spectrum β-lactamase Family Fiber Funding Generations Goals Gram-Negative Bacteria Habitats Health Healthcare Human Human Development Immunologist Immunology Infection Investigational Therapies Klebsiella Knowledge Lead Life Ligands Mannose Mannosides Mediating Medicine Membrane Microbiology Molecular Molecular Chaperones Monoclonal Antibodies Multi-Drug Resistance Multidrug-resistant Acinetobacter Multiple Bacterial Drug Resistance Nosocomial Infections Pathogenesis Pathogenicity Pathway interactions Patients Permeability Pharmaceutical Chemistry Phase Ia/Ib Clinical Trial Pilum Process Pyridones Recurrence Resistance Savings Scientist Streptococcus Group B Streptococcus pneumoniae Streptococcus pyogenes Structure Surface Testing Therapeutic Therapeutic Monoclonal Antibodies Time Translating United States National Institutes of Health Universities Urinary tract infection Uropathogenic E. coli Usher Proteins Vaccines Vancomycin resistant enterococcus Virulence Washington Work analog antibiotic resistant infections bactericide base carbapenem resistance carbapenem-resistant Enterobacteriaceae catheter associated UTI clinical development combat combinatorial chemistry community-acquired UTI design drug discovery drug resistant pathogen extracellular glycomimetics in vivo innovation insight interdisciplinary approach medical schools meetings member methicillin resistant Staphylococcus aureus microbial mimetics multi-drug resistant pathogen neutralizing monoclonal antibodies novel pathogen pathogenic bacteria peptidomimetics pressure prevent programs rational design receptor resistance mechanism small molecule small molecule inhibitor small molecule therapeutics sortase structural biology success therapy development tool

项目摘要

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.

项目摘要/摘要：对我们救生的抗生素库不再敏感的抗生素耐药性细菌感染是一种迫在眉睫的灾难以及最近的 COVID-19 危机，如果我们没有准备好。该提案利用基础科学发现来开发抗生素节约药物对疾病预防控制中心指定的对人类健康构成威胁的大多数病原体的治疗有影响的药物。项目 1 和 2 针对表达粘附菌毛的多重耐药 (MDR) 革兰氏阴性病原体在涉及急性和慢性/复发性尿路的宿主栖息地定植和感染所需感染 (UTI) 和导管相关性尿路感染 (CAUTI)，包括耐多药不动杆菌、碳青霉烯类耐药菌肠杆菌科 (CRE) 和产超广谱 β-内酰胺酶 (ESBL) 肠杆菌科。项目 2 在此列表上进行了扩展，将其他值得关注的革兰氏阴性病原体包括在内。由于尿路感染占人类约 10% 的抗生素使用量，开发节省抗生素的疗法不仅可以让治疗抗生素耐药性感染，但通过减少现有抗生素的使用，将降低选择性抵抗的压力。项目 1 的重点是使用糖模拟物中和细菌菌毛粘附素 CORE 1 中设计的单克隆抗体和 CORE 2 中开发的单克隆抗体将阻断细菌之间的关键相互作用粘附素及其宿主配体。糖模拟物在中和伴侣/引座子方面显示出巨大的前景途径（CUP）体内粘附素来治疗疾病。例如，甘露糖苷，可以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 的有效疗法，因为 FimH 是治疗和预防 UTI 所必需的 UPEC 定植于膀胱。与葛兰素史克合作，选择甘露糖苷进入 1a/1b 期临床试验，从而验证该策略的潜力。治疗性单克隆抗体具有尚未完全用于治疗传染病。随着抗生素耐药性的增加，是时候采取措施了应用这个策略。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 CAUTI，并且通常是 MDR。项目 2 将使用类似的工具来关注 CUP 机械，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 Gram- 通过进一步开发 GmPcides，CDC 将阳性物种确定为重大威胁，GmPcides 是一种新型稠环 2-吡啶酮化合物家族，对广谱革兰氏菌具有杀菌作用阳性种。 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治疗药物开发中的应用（核心1）及应用针对细菌蛋白的高通量单克隆抗体生成 (CORE 2)。综合知识、专业知识项目和核心领导者的成功将促进抗生素节约的发展治疗越来越多的抗生素耐药性病原体，以避免其返回在抗生素出现之前的时代，常见的感染基本上是无法治疗的。