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

项目摘要/摘要： 新冠肺炎周围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 对我们救命的抗生素武器库不再敏感。因此，这个项目被用来翻译基本的 针对美国最常见的细菌感染之一，科学转化为节省抗生素的药物， 尿路感染(UTI)，以及最常见的与导尿管相关的医院获得性感染 UTI(CAUTI)。其策略是开发出对碳青霉烯耐药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)的肠杆菌科， 包括80%以上的社区获得性尿路感染的原因，尿路致病性大肠埃希菌(UPEC)。CAUTIS 对全球医疗保健构成重大挑战。虽然UPEC导致50%的CAUTI，但其他病原体， 包括产超广谱β-内酰胺酶和克雷伯氏菌、耐多药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)在内，引起CAUTIs的比例很大。这些MDR 病原体表达在不同宿主生境中定居和感染所需的黏附因子 急性和慢性/复发性尿路感染以及慢性尿路感染。小分子和单抗(MAbbs) 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。通过 在细胞外发挥作用，这些节省抗生素的疗法将顽固地抵抗细胞内的机制 在小分子药物的发现中，避免了细胞通透性的常见障碍。UPEC， 克雷伯氏菌和不动杆菌表达粘附素末端的伴侣引导途径(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 膀胱定植(FimH)、膀胱和肾脏炎症(FmlH)、肠道定植(FimH、UclD和Yehd)和 导管(FimH和CupD)。此外，粪肠球菌表达EBPA-TIP-Sortase组装菌毛， 它们在CAUTI中是至关重要的。GlycoMimtics在体内中和杯状粘附素方面显示出巨大的希望 治病。例如，中和FimH功能的甘露糖苷是治疗的有效疗法。 预防尿路感染，因为FimH是UPEC定植膀胱所必需的。验证此文件中的工作 建议，已经与葛兰素史克合作，选择了甘露糖苷进入1a/ab期临床试验。 在人类身上。此外，一种FimH疫苗已经完成了1a/1b期临床试验。单抗的使用有 革命性地治疗癌症、炎症性和神经性疾病。治疗性单抗还没有 被充分利用来治疗传染病，可能要归功于抗生素的历史性成功。在这 项目，我们将开发治疗性mAb，旨在通过中和来防止关键的宿主-病原体相互作用 上述粘附素。联合战略有可能产生变革性的 节省抗生素的治疗方法，对抗生素敏感和耐药感染同样有效。

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.