Novel therapeutics for treatment of catheter-associated UTI and depletion of the vaginal reservoir

项目总结/摘要 抗生素耐药性（AMR）每年在全球造成约500万人死亡，并直接影响到全球的健康。 造成超过120万人死亡。在不远的将来，我们可能会面临一个现实， 对现有的所有抗生素都有抗药性是很常见的。因此，解决抗菌素耐药性， 开发保瘤疗法是一个紧迫的全球健康问题。尿路感染（UTI） 占所有抗生素处方的15%以上，并直接促进了AMR细菌的发展。一 用于UTI的潜在的抗肿瘤治疗剂是单克隆抗体（mAb）， 已成功部署数十年，并具有强大的安全性和有效性历史。的目的 目前的建议是开发针对两种类型UTI的mAb，这两种类型的UTI极大地增加了全球疾病负担。整体 假设是针对细菌菌毛粘附素蛋白的mAb将阻断粘附素-配体相互作用， 防止细菌粘附于宿主组织。在目标1中，将探索单克隆抗体作为导管- 由两种经常具有多重耐药性的病原体引起的相关性UTI：肠球菌 粪肠杆菌和鲍曼不动杆菌。这些细菌通过使用粘性粘附素结合到 纤维蛋白原沉积在导尿管表面。单克隆抗体将阻断这种相互作用，以防止导管 殖民化在目标2中，将检测mAb阻断细菌与宿主组织相互作用的能力。 尿路致病性大肠杆菌（UPEC）经常引起高度复发性UTI（鲁蒂），部分原因是建立了 胃肠道和阴道中的储库，作为UPEC持续再引入的来源 进入膀胱腔虽然负责肠道定植的粘附素已被表征， 负责阴道定殖的粘附素是未知的。根据现有数据， 阴道中的UPEC S菌毛，将首先阐明该菌毛对阴道定殖的贡献。mAbs 然后将产生S菌毛粘附素，并测试它们从阴道消耗UPEC的能力。的 这项研究的长期目标是产生可以治疗人类尿路感染的单克隆抗体。 在奖学金期间，申请人将发展成为独立调查员的重要技能， 传染病这项工作的发起人，斯科特Hultgren博士，有丰富的经验，研究泌尿道 感染的发病机制和治疗，以及制度环境提供支持，协作 微生物学和免疫学专家。华盛顿大学医学院有着悠久的历史， 帮助医生科学家建立成功的职业生涯。拟议的培训计划将有助于申请人 转变为一个独立的医生，科学家，利用研究来改善妇女的健康。

PROJECT SUMMARY / ABSTRACT Antimicrobial resistance (AMR) contributes to an estimated 5 million deaths worldwide each year and is directly responsible for over 1.2 million deaths. In the not-to-distant future, we may face a reality where infections resistant to all existing antibiotics are commonplace. Therefore, addressing antimicrobial resistance by developing antibiotic-sparing therapeutics is an urgent global health concern. Urinary tract infections (UTI) drive over 15% of all antibiotic prescriptions and directly contribute to the development of AMR bacteria. One potential antibiotic-sparing therapeutic for UTIs is monoclonal antibodies (mAbs), which have been successfully deployed for decades and have a strong history of safety and efficacy. The objective of this proposal is to develop mAbs to two types of UTIs that greatly contribute to global disease burden. The overall hypothesis is that mAbs to bacterial pilus adhesin proteins will block adhesin-ligand interactions and thus prevent bacterial adherence to host tissues. In Aim 1, mAbs will be explored as a treatment for catheter- associated UTI (CAUTI) caused by two pathogens that are frequently multi-drug resistant: Enterococcus faecalis and Acinetobacter baumannii. These bacteria cause CAUTI by using sticky adhesins to bind to fibrinogen deposited on the surface of urinary catheters. mAbs will block this interaction to prevent catheter colonization. In Aim 2, mAbs will be tested for their ability to block bacterial interaction with host tissue. Uropathogenic Escheriscia coli (UPEC) frequently causes highly recurrent UTI (rUTI) in part by establishing reservoirs in the gastrointestinal tract and vagina that serve as a source for UPEC’s continuous reintroduction into the bladder lumen. While the adhesins responsible for gut colonization have been characterized, the adhesin responsible for vaginal colonization is unknown. Based on existing data suggesting a role for the UPEC S pilus in the vagina, the contribution of this pilus to vaginal colonization will first be elucidated. mAbs will then be generated to the S pilus adhesin and tested for their ability to deplete UPEC from the vagina. The long-term goal of the proposed research is to generate mAbs that can treat human urinary tract infections. During the fellowship, the applicant will develop important skills for becoming an independent investigator of infectious diseases. The sponsor of this work, Dr. Scott Hultgren, has vast experience studying urinary tract infection pathogenesis and treatment, and the institutional environment provides supportive, collaborative experts in microbiology and immunology. Washington University School of Medicine has a long history of helping physician-scientists build successful careers. The proposed training plan will facilitate the applicant’s transition into becoming an independent physician-scientist, using research to improve women’s health.