Innovative Strategies to Combat Antibiotic-resistant Infections

对抗抗生素耐药性感染的创新策略

• 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
• 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

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： 不再对我们的救生抗生素武器敏感的抗生素耐药细菌感染是一种 迫在眉睫的灾难以及最近的Covid-19危机，如果我们将对人类健康产生可怕的后果 没有准备。该提案利用基础科学发现来开发抗生素的比例 疾病预防控制中心对大多数病原体指定对人类健康的威胁的治疗产生影响的药物。 项目1和2目标多药耐药（MDR）革兰氏阴性病原体表达粘合剂pili 涉及急性和慢性/经常性尿路的宿主栖息地中定植和感染所必需的 感染（UTI）和与导管相关的UTI（CAUTIS），包括MDR ACINETOBACTER，耐碳青霉烯 肠杆菌科（CRE）和扩展的谱β-内酰胺酶（ESBL） - 产生肠杆菌科。 项目2在此列表中扩展，以包括其他关注的革兰氏阴性病原体。由于UTIS帐户 约10％的抗生素在人类中使用，抗生素疗法的发展不仅允许 抗生素耐药性感染的治疗，但通过减少当前抗生素的使用，将降低选择性 阻力压力。项目1的重点是使用糖胶质中和细菌皮质粘附素 在Core 1和Core 2中开发的MAB中设计的，该MAB将阻止细菌之间的关键相互作用 胶粘剂及其宿主配体。 Glycomimimitics在中和伴侣/usher方面表现出了巨大的希望 体内途径（杯）粘合剂治疗疾病。例如，甘露糖苷（中和肌发育。 大肠杆菌（UPEC）粘附素FIMH是治疗和预防UTI的有效治疗方法，因为FIMH需要 UPEC殖民膀胱。与GlaxoSmithkline合作，已选择了甘露糖苷 继续进行1A/1B期临床试验，从而验证了该策略的潜力。治疗性mab具有 尚未完全利用治疗传染病。随着抗生素抗性的上升，是时候了 应用此策略。项目1还将针对革兰氏阳性肠球菌的分类酶组装的皮质粘合剂， 这会导致小肠，通常是MDR。项目2将使用类似的工具专注于杯子机械 在Pilus纤维尖端组装项目1中的革兰氏阴性粘合剂。项目3将针对所有革兰个 通过疾病预防疾病鉴定为阳性物种是通过促进GMPCIDES的发展，A的阳性物种 新型环融合的2-吡啶酮化合物，它们是针对革兰氏阴性 积极物种。核心将与提供计算和的科学项目完全集成 在小分子疗法开发中的合成药物（核心1）和应用 针对细菌蛋白的高吞吐量mAb产生（核心2）。合并知识，专业知识 项目和核心领导者的成功将导致抗生素保存的发展 治疗日益增长的抗生素耐药病原体的治疗剂，以避免回归 当常见感染基本上无法治疗的抗生素时代。