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
基本信息
- 批准号:10605022
- 负责人:
- 金额:$ 3.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Acinetobacter baumanniiAddressAdherenceAdhesivesAntibiotic TherapyAntibioticsAntimicrobial ResistanceBacteriaBacterial AdhesinsBindingBladderBladder UrotheliumCOVID-19CatalogsCatheterizationCathetersCessation of lifeChronicCommunicable DiseasesDataDepositionDevelopmentDiseaseDistantDoseEnterococcusEnterococcus faecalisEnvironmentEpithelial CellsEpitheliumFellowshipFemaleFibrinogenFutureGastrointestinal tract structureGenesGoalsHumanImmunityImmunizationImmunizeImmunofluorescence ImmunologicImmunologyIn VitroInfectionInfective cystitisInflammatory ResponseInstitutionLigandsMediatingMicrobial BiofilmsMicrobiologyModelingMonitorMonoclonal AntibodiesMulti-Drug ResistanceMusNaturePathogenesisPhysiciansPilumPlayPreventionProtein SubunitsProteinsQuality of lifeRecording of previous eventsRecurrenceReproductive Tract InfectionsResearchResearch PersonnelResistanceResistance developmentRoleSafetyScientistSourceSpecificitySurfaceTestingTherapeuticTissue StainsTissuesTrainingUnited StatesUniversitiesUrethraUrinary tract infectionUropathogenUropathogenic E. coliVaginaVirulence FactorsWashingtonWomanWomen&aposs HealthWorkappendagebacterial resistanceburden of illnesscareercatheter associated UTIexperienceexperimental studyglobal healthgut colonizationimprovedin vivoindexingmedical schoolsmouse modelmutantnovel therapeuticspathogenpreventprophylacticprotective effectrecurrent infectionreproductive tractsexskillssuccesstherapeutic targeturinary
项目摘要
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.
项目概要/摘要
抗菌素耐药性 (AMR) 每年导致全球约 500 万人死亡,并直接导致
在不远的将来,我们可能会面临感染的现实。
因此,对所有现有抗生素产生耐药性是很常见的。
开发节省抗生素的疗法是全球紧迫的健康问题。
占所有抗生素处方的 15% 以上,并直接促进 AMR 细菌的发展。
单克隆抗体 (mAb) 是治疗尿路感染的潜在抗生素节约疗法,该抗体已被
已成功部署数十年,并具有良好的安全性和有效性的历史。
建议开发针对两种类型的尿路感染的单克隆抗体,这两种类型的尿路感染对全球疾病负担有很大影响。
假设针对细菌菌毛粘附素蛋白的单克隆抗体会阻断粘附素-配体相互作用,从而
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-的治疗方法。
由两种经常具有多重耐药性的病原体引起的相关性尿路感染 (CAUTI):肠球菌
粪肠球菌和鲍曼不动杆菌这些细菌通过使用粘性粘附素来引起 CAUTI。
沉积在导尿管表面的纤维蛋白原会阻断这种相互作用,从而防止导尿管发生。
在目标 2 中,将测试单克隆抗体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) 经常导致高度复发性尿路感染 (rUTI),部分原因是建立
胃肠道和阴道中的储存库是 UPEC 持续重新引入的来源
虽然负责肠道定植的粘附素已被表征,但
根据现有数据,粘附素负责阴道定植的作用尚不清楚。
UPEC S 菌毛在阴道中,首先将阐明该菌毛对阴道定植的贡献。
然后将生成 S 菌毛粘附素并测试其从阴道消耗 UPEC 的能力。
拟议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,申请人将培养成为独立调查员的重要技能
这项工作的发起人 Scott Hultgren 博士在泌尿道研究方面拥有丰富的经验。
感染发病机制和治疗,以及机构环境提供支持性、协作性
华盛顿大学医学院拥有悠久的微生物学和免疫学专家。
帮助医生科学家建立成功的职业生涯。拟议的培训计划将促进申请人的发展。
转变为一名独立的医师科学家,利用研究来改善女性的健康。
项目成果
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