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

治疗导管相关性尿路感染和阴道储库耗竭的新疗法

• 批准号: 10605022
• 负责人: Morgan Rose Wilt Timm
• 金额: $ 3.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-10 至 2026-02-09
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605022
• 关键词: Acinetobacter baumannii; Address; Adherence; Adhesives; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Bacteria; Bacterial Adhesins; Binding; Bladder; Bladder Urothelium; COVID-19; Catalogs; Catheterization; Catheters; Cessation of life; Chronic; Communicable Diseases; Data; Deposition; Development; Disease; Distant; Dose; Enterococcus; Enterococcus faecalis; Environment; Epithelial Cells; Epithelium; Fellowship; Female; Fibrinogen; Future; Gastrointestinal tract structure; Genes; Goals; Human; Immunity; Immunization; Immunize; Immunofluorescence Immunologic; Immunology; In Vitro; Infection; Infective cystitis; Inflammatory Response; Institution; Ligands; Mediating; Microbial Biofilms; Microbiology; Modeling; Monitor; Monoclonal Antibodies; Multi-Drug Resistance; Mus; Nature; Pathogenesis; Physicians; Pilum; Play; Prevention; Protein Subunits; Proteins; Quality of life; Recording of previous events; Recurrence; Reproductive Tract Infections; Research; Research Personnel; Resistance; Resistance development; Role; Safety; Scientist; Source; Specificity; Surface; Testing; Therapeutic; Tissue Stains; Tissues; Training; United States; Universities; Urethra; Urinary tract infection; Uropathogen; Uropathogenic E. coli; Vagina; Virulence Factors; Washington; Woman; Women' s Health; Work; appendage; bacterial resistance; burden of illness; career; catheter associated UTI; experience; experimental study; global health; gut colonization; improved; in vivo; indexing; medical schools; mouse model; mutant; novel therapeutics; pathogen; prevent; prophylactic; protective effect; recurrent infection; reproductive tract; sex; skills; success; therapeutic target; urinary; Acinetobacter baumannii; Address; Adherence; Adhesives; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Bacteria; Bacterial Adhesins; Binding; Bladder; Bladder Urothelium; COVID-19; Catalogs; Catheterization; Catheters; Cessation of life; Chronic; Communicable Diseases; Data; Deposition; Development; Disease; Distant; Dose; Enterococcus; Enterococcus faecalis; Environment; Epithelial Cells; Epithelium; Fellowship; Female; Fibrinogen; Future; Gastrointestinal tract structure; Genes; Goals; Human; Immunity; Immunization; Immunize; Immunofluorescence Immunologic; Immunology; In Vitro; Infection; Infective cystitis; Inflammatory Response; Institution; Ligands; Mediating; Microbial Biofilms; Microbiology; Modeling; Monitor; Monoclonal Antibodies; Multi-Drug Resistance; Mus; Nature; Pathogenesis; Physicians; Pilum; Play; Prevention; Protein Subunits; Proteins; Quality of life; Recording of previous events; Recurrence; Reproductive Tract Infections; Research; Research Personnel; Resistance; Resistance development; Role; Safety; Scientist; Source; Specificity; Surface; Testing; Therapeutic; Tissue Stains; Tissues; Training; United States; Universities; Urethra; Urinary tract infection; Uropathogen; Uropathogenic E. coli; Vagina; Virulence Factors; Washington; Woman; Women' s Health; Work; appendage; bacterial resistance; burden of illness; career; catheter associated UTI; experience; experimental study; global health; gut colonization; improved; in vivo; indexing; medical schools; mouse model; mutant; novel therapeutics; pathogen; prevent; prophylactic; protective effect; recurrent infection; reproductive tract; sex; skills; success; therapeutic target; urinary

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.

项目摘要 /摘要 抗菌耐药性（AMR）每年估计有500万人死亡，直接是 负责超过120万人死亡。在不偏见的未来，我们可能会面临感染的现实 对所有现有抗生素的抗药性都是司空见惯的。因此，通过 开发抗生素的疗法是一个紧急的全球健康问题。尿路感染（UTI） 驱动所有抗生素处方的15％以上，直接有助于AMR细菌的发展。一 UTI的潜在抗生素疗法是单克隆抗体（mAb），它已经 成功地部署了数十年，并具有悠久的安全性和有效性的历史。这个目的 提议是为两种类型的UTI开发MAB，这些UTI极大地造成了全球疾病负担。总体 假设是对细菌pyrus粘附素蛋白的mAb会阻塞粘附素 - 配体相互作用，从而阻止 防止细菌依从性宿主组织。在AIM 1中，将探索mAB作为导管的治疗方法 相关的UTI（CAUTI）是由两种经常具有多药的病原体引起的：肠球菌 粪便和鲍曼尼杆菌。这些细菌通过使用粘附的粘附与 纤维蛋白原沉积在尿导管表面。 mABS将阻止这种相互作用以防止导管 殖民化。在AIM 2中，将测试mAB的测试能力阻止细菌与宿主组织的相互作用。 肝癌大肠杆菌（UPEC）经常通过建立高度复发的UTI（RUTI）。 胃肠道和阴道中的水库，这些储量是UPEC连续重新引入的来源 进入膀胱腔。虽然已经表征了负责肠道定植的粘附素，但 导致阴道定植的粘附素尚不清楚。基于现有数据，暗示了 upec spilus在阴道中，该二氧化硅对阴道定植的贡献将首先阐明。 mabs 然后将生成Spilus粘连蛋白，并测试其从阴道中复制UPEC的能力。 拟议的研究的长期目标是产生可以治疗人类尿路感染的mAB。 在奖学金期间，申请人将发展重要技能，成为成为独立研究者 传染病。这项工作的赞助商Scott Hultgren博士在研究尿路方面拥有丰富的经验 感染发病机理和治疗，机构环境提供了支持，协作的 微生物学和免疫学专家。华盛顿大学医学院有悠久的历史 帮助身体科学家建立成功的职业。拟议的培训计划将促进申请人的 过渡到成为独立的身体科学家，利用研究来改善妇女的健康。