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

项目总结/摘要： 围绕COVID-19的气候戏剧性地提醒我们， 对健康危机毫无准备。一个迫在眉睫的健康危机是抗药性细菌感染的激增 对我们的救命抗生素库不再敏感。因此，该项目被用来翻译基本的 在美国，一种最常见的细菌感染， 尿路感染（UTI），以及最常见的医院获得性感染，导管相关性感染， 尿路感染（尿路感染）。该策略是开发对碳青霉烯类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， 包括引起超过80%的社区获得性UTI的致病性大肠杆菌（UPEC）。Patients 对全球医疗保健构成重大挑战。虽然UPEC导致50%的ESTTI，但其他病原体， 包括ESBL和CRE克雷伯菌、多重耐药（MDR）不动杆菌和革兰氏阳性肠球菌 包括万古霉素抗性肠球菌（VRE），引起显著比例的肠炎。这些MDR 病原体在不同的宿主生境中表达定殖和感染所需的粘附因子， 急性和慢性/复发性UTI以及急性UTI。小分子和单克隆抗体（mAb） 将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。通过 在细胞外起作用，这些抗肿瘤治疗剂将不受细胞内机制的影响， 并避免了小分子药物发现中常见的细胞通透性障碍。UPEC， 克雷伯氏菌属和不动杆菌属表达以粘附素为顶端的伴侣引导途径（CUP）皮利：i）FimH， FmlH、YehD、UclD（UPEC）; ii）FimH（克雷伯氏菌属）和iii）CupD（不动杆菌属）。这些粘附素对于 膀胱（FimH）、发炎的膀胱和肾脏（FmlH）、肠道（FimH、UclD和YehD）的定殖，以及 导管（FimH和CupD）。此外，粪肠球菌表达EbpA末端分选酶组装的皮利， 这在CITTI中至关重要。糖模拟物在体内中和CUP粘附素方面显示出很大的前景， 治疗疾病。例如，中和FimH功能的甘露糖苷是治疗FimH的有效治疗剂。 和预防UTI，因为UPEC需要FimH来定殖膀胱。在此验证工作 根据一项建议，与GSK合作，选择了一种甘露糖苷进行1a/ab期临床试验 在人类身上。此外，FimH疫苗已完成1a/1b期临床试验。单克隆抗体的使用 革命性地治疗癌症、炎症和神经元疾病。治疗性单克隆抗体尚未 被充分利用来治疗传染病，也许是由于抗生素的历史性成功。在这 项目，我们将开发治疗性单克隆抗体，旨在防止关键的宿主-病原体相互作用， 上面描述的粘附素。综合战略有可能产生变革性的 对抗生素敏感和耐药感染同样有效的抗生素保留疗法。

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.