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

项目摘要/摘要 抗菌素耐药性(AMR)每年在全球范围内造成约500万人死亡，并直接导致 造成120多万人死亡。在不远的将来，我们可能会面临一个现实，感染 对所有现有抗生素产生抗药性是司空见惯的。因此，通过以下方式解决抗菌素耐药性 开发节省抗生素的疗法是一个紧迫的全球健康问题。尿路感染(UTI) 推动了超过15%的抗生素处方，并直接促进了AMR细菌的发展。一 尿路感染的潜在节省抗生素的治疗方法是单抗(MAbbs)，它已经 成功部署了几十年，并有很强的安全性和有效性历史。这样做的目的是 建议将单抗发展为两种类型的尿路感染，这两种类型的尿路感染极大地增加了全球疾病负担。整体而言 假设针对细菌菌毛粘附素蛋白的单抗将阻断粘附素与配体的相互作用，从而 防止细菌附着在宿主组织上。在目标1中，将探索单抗作为导管的治疗方法。 由两种经常多重耐药的病原体引起的相关性尿路感染：肠球菌 粪便杆菌和鲍曼不动杆菌。这些细菌通过使用粘附素结合到 纤维蛋白原沉积在导尿管表面。单抗将阻断这种相互作用以防止导管 殖民主义。在目标2中，将测试单抗是否有能力阻止细菌与宿主组织的相互作用。 尿路致病性大肠埃希菌(UPEC)经常引起高度复发的尿路感染(RUTI)，部分原因是通过建立 胃肠道和阴道的蓄水池是UPEC持续重新引入的来源 进入膀胱腔。虽然导致肠道定植的粘附素已经被表征，但 粘附素对阴道定植的作用尚不清楚。根据现有数据显示， UPEC S在阴道中的菌毛，这种菌毛对阴道定植的贡献将首先被阐明。单抗 然后会生成粘附素到S菌毛，并测试它们从阴道中排出UPEC的能力。这个 这项拟议研究的长期目标是产生能够治疗人类尿路感染的单抗。 在奖学金期间，申请者将发展成为一名独立调查员的重要技能 传染病。这项工作的发起人Scott Hultgren博士在研究尿路方面有丰富的经验 感染的发病机制和治疗，以及制度环境提供的支持、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 帮助内科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者 转变为独立的内科医生兼科学家，利用研究改善妇女的健康。

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.