Development of anti-adhesin mAbs and high-affinity ligand mimetics to treat and prevent UTIs

开发抗粘附素单克隆抗体和高亲和力配体模拟物来治疗和预防尿路感染

基本信息

批准号：
10577806
负责人：
SCOTT J. HULTGREN
金额：
$ 37.79万
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/10577806
关键词：
Acinetobacter Acute Adhesives Affinity Antibiotic Resistance Antibiotics Antibodies Antibody Therapy Bacteria Bacterial Adhesins Bacterial Antibiotic Resistance Bacterial Infections Basic Science Binding Biological Availability Bladder COVID-19 Catheters Cell Wall Cells Chronic Chronic Cystitis Climate Clinical Treatment Clinical Trials Collaborations Communicable Diseases Development Disease Enterobacteriaceae Enterococcus Enterococcus faecalis Extended-spectrum β-lactamase Fibrinogen Funding Galactose Gastrointestinal tract structure Gram-Negative Bacteria Habitats Health Healthcare Human In Vitro Indwelling Catheter Infection Inflammatory Ingestion Invaded Kidney Klebsiella Klebsiella pneumoniae Knowledge Life Ligands Longevity Mannose Mannosides Medicine Microbial Biofilms Modeling Molecular Chaperones Monoclonal Antibodies Multidrug-resistant Acinetobacter Neurons Nosocomial Infections Oral Pathogenicity Pathway interactions Pectins Permeability Phase Phase Ia/Ib Clinical Trial Pilum Plants Pre-Clinical Model Privatization Recurrence Resistance Resistance profile Resources Structure-Activity Relationship Surface Testing Therapeutic Therapeutic Monoclonal Antibodies Tissues Translating United States Urinary tract infection Uropathogen Uropathogenic E. coli Vaccines Vancomycin Resistance Vancomycin resistant enterococcus Work antagonist antibiotic resistant infections bacterial community cancer therapy candidate identification carbapenem-resistant Enterobacteriaceae catheter associated UTI combat community-acquired UTI design diabetic drug discovery drug resistant pathogen experimental study extracellular gastrointestinal global health glycomimetics gut colonization host colonization implant coating implantation in vivo innovation mimetics mouse model multi-drug resistant pathogen pathogen pressure prevent programs receptor residence resistance mechanism small molecule sortase success wound

项目摘要

PROJECT SUMMARY/ABSTRACT: The climate surrounding COVID-19 has dramatically reminded us of the dire consequences of being unprepared for health crises. One looming health crisis is the surge of antibiotic-resistant bacterial infections that are no longer sensitive to our life saving antibiotic arsenal. Thus, this project is leveraged to translate basic science into antibiotic-sparing medicines for one of the most common bacterial infections in the United States, urinary tract infections (UTIs), as well as the most common hospital-acquired infection, catheter-associated UTIs (CAUTIs). The strategy is to develop therapeutics that work equally well against carbapenem-resistant Enterobacteriaceae (CRE) and extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae, including the cause of over 80% of community-acquired UTIs, uropathogenic Escherichia coli (UPEC). CAUTIs pose a significant challenge for healthcare globally. While UPEC causes 50% of CAUTI, other pathogens, including ESBL and CRE Klebsiella, multidrug resistant (MDR) Acinetobacter and Gram-positive Enterococcus including vancomycin resistant Enterococcus (VRE), cause a significant proportion of CAUTIs. These MDR pathogens express adhesive factors required for colonization and infection in different host habitats involved in acute and chronic/recurrent UTIs as well as in CAUTIs. Small molecules and monoclonal antibodies (mAbs) will be developed that will treat and prevent disease by blocking these critical host-pathogen interactions. By acting extracellularly, these antibiotic-sparing therapeutics will be recalcitrant to intracellular mechanisms of resistance and avoid a common obstacle of cell permeability in drug discovery of small molecules. UPEC, Klebsiella and Acinetobacter express chaperone usher pathway (CUP) pili tipped with adhesins: i) FimH, FmlH, YehD, UclD (UPEC); ii) FimH (Klebsiella) and iii) CupD (Acinetobacter). These adhesins are critical for colonization of the bladder (FimH), inflamed bladder and kidney (FmlH), gut (FimH, UclD and YehD) and catheters (FimH and CupD). Further, Enterococcus faecalis express EbpA-tipped sortase-assembled pili, which are critical in CAUTI. Glycomimetics have shown great promise in neutralizing CUP adhesins in vivo to treat disease. For example, mannosides which neutralize FimH function, are potent therapeutics for treating and preventing UTI, since FimH is required by UPEC to colonize the bladder. Validating the work in this proposal, a mannoside has been selected, in collaboration with GSK, to proceed into phase 1a/ab clinical trials in humans. Also, a FimH vaccine has completed Phase 1a/1b clinical trials. The use of mAbs has revolutionized treatments for cancer, inflammatory, and neuronal disorders. Therapeutic mAbs have not yet been fully harnessed for treating infectious diseases, perhaps due to the historic success of antibiotics. In this project, we will develop therapeutic mAb designed to prevent critical host-pathogen interactions by neutralizing the adhesins described above. The combined strategies have the potential to produce transformative antibiotic-sparing therapeutics that work equally well against and antibiotic-sensitive and resistant infections.

项目概要/摘要： COVID-19 周围的气候戏剧性地提醒我们，如果对健康危机没有做好准备。一场迫在眉睫的健康危机是抗生素耐药性细菌感染的激增它们对我们救命的抗生素不再敏感。因此，该项目被用来翻译基本的科学研究发现针对美国最常见的细菌感染之一的抗生素节约药物，尿路感染 (UTI)，以及最常见的医院获得性感染、导尿管相关感染尿路感染（CAUTI）。该策略是开发对碳青霉烯类药物耐药性同样有效的治疗方法肠杆菌科 (CRE) 和产超广谱 β-内酰胺酶 (ESBL) 肠杆菌科，其中包括超过 80% 的社区获得性尿路感染的病因——尿路致病性大肠杆菌 (UPEC)。类风湿性关节炎对全球医疗保健构成重大挑战。虽然 50% 的 CAUTI 是由 UPEC 引起的，但其他病原体，包括 ESBL 和 CRE 克雷伯氏菌、多重耐药 (MDR) 不动杆菌和革兰氏阳性肠球菌包括万古霉素耐药肠球菌 (VRE)，导致很大一部分 CAUTI。这些MDR 病原体表达在不同宿主栖息地定植和感染所需的粘附因子急性和慢性/复发性尿路感染以及 CAUTI。小分子和单克隆抗体 (mAb) 将开发出通过阻断这些关键的宿主-病原体相互作用来治疗和预防疾病的药物。经过由于在细胞外起作用，这些抗生素节约疗法将难以抵抗细胞内的机制耐药性并避免小分子药物发现中细胞渗透性的常见障碍。统一经济共同体，克雷伯氏菌和不动杆菌表达末端带有粘附素的伴侣引导通路 (CUP) 菌毛：i) FimH， FmlH、YehD、UCLD (UPEC)； ii) FimH（克雷伯氏菌）和 iii) CupD（不动杆菌）。这些粘附素对于膀胱定植 (FimH)、膀胱和肾脏发炎 (FmlH)、肠道（FimH、UclD 和 YehD）和导管（FimH 和 CupD）。此外，粪肠球菌表达 EbpA 末端分选酶组装的菌毛，这对于 CAUTI 至关重要。糖模拟物在体内中和 CUP 粘附素方面显示出巨大的前景治疗疾病。例如，中和 FimH 功能的甘露糖苷是治疗以下疾病的有效疗法：预防 UTI，因为 UPEC 需要 FimH 才能在膀胱中定植。验证本次工作根据提案，与葛兰素史克合作，选择了一种甘露糖苷，进入 1a/ab 期临床试验在人类中。此外，FimH疫苗已完成1a/1b期临床试验。单克隆抗体的使用彻底改变了癌症、炎症和神经元疾病的治疗方法。治疗性单克隆抗体尚未出现或许得益于抗生素的历史性成功，抗生素已被充分用于治疗传染病。在这个项目中，我们将开发治疗性单克隆抗体，旨在通过中和来预防关键的宿主-病原体相互作用上述粘附素。组合战略有可能产生变革性的成果节省抗生素的疗法对抗生素敏感和耐药感染同样有效。