Beta-Lactamase Inhibitors Sensitize Multidrug-Resistant Gram-negative Pathogens to Innate Immune Clearance

β-内酰胺酶抑制剂使多重耐药革兰氏阴性病原体对先天免疫清除敏感

基本信息

批准号：
10239264
负责人：
Erlinda Rose Ulloa
金额：
$ 20.53万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10239264
关键词：
Address Affinity Anti-Bacterial Agents Antibiotic Resistance Antibiotic Therapy Antibiotics Award Bacterial Infections Binding Binding Proteins Biological Assay Blood Platelets Boston California Cations Cell Death Cell Wall Cell membrane Cell surface Cells Characteristics Childhood Clinical Combating Antibiotic Resistant Bacteria Communicable Diseases Complement Cytolysis DNA Development Dose Drug resistance Electrostatics Epithelial Cells Equilibrium FDA approved Faculty Fellowship Fluorescence Microscopy Foundations Genetic Genomics Goals Hemophilus Histopathology Immune Immunity Immunology Immunotherapy In Vitro Infection Inflammation Innate Immune System Investigational Therapies Klebsiella Klebsiella pneumoniae Knock-out Life Lipids Logic Manuscripts Membrane Mentors Microbe Microscopy Modeling Modern Medicine Morphology Multi-Drug Resistance Multiple Bacterial Drug Resistance Mus Natural Immunity Pathogenesis Patient-Focused Outcomes Patients Pattern Pediatric Hospitals Pediatrics Penicillin Binding Protein 2 Penicillin-Binding Proteins Peptide Antibiotics Peptides Peptidoglycan Peptidyltransferase Phagocytosis Pharmaceutical Preparations Pharmacologic Substance Pharmacology Philadelphia Physicians Predisposition Prevalence Production Proteins Pseudomonas Public Health RNA Research Research Personnel Residencies Resistance Resolution Resources Respiratory Burst Rod Safety Scientist Serial Passage Shapes Structure Surface Properties Teacher Professional Development Therapeutic Toxic effect Training Training Programs Treatment outcome Universities Vision Vocational Guidance antimicrobial antimicrobial peptide bacterial genetics bacterial resistance bactericide base beta-Lactamase career combat cytokine drug discovery drug repurposing drug resistant pathogen emerging antimicrobial resistance extracellular fitness genome sequencing immune clearance immunoregulation improved in vivo inhibitor/antagonist innovation medical schools mouse model multi-drug resistant pathogen mutant neutrophil novel novel therapeutic intervention novel therapeutics pathogen peptide I pneumonia model professor resistance mutation resistant Klebsiella pneumoniae response skills synergism therapeutic target treatment strategy whole genome working group

项目摘要

Project Summary The goal of the proposed five-year training program is to support the development of the applicant's independent research career as an academic pediatric infectious diseases doctor focused on host-directed therapeutics for multidrug-resistant pathogens. The applicant completed medical school at Stanford University School of Medicine, pediatrics residency training at Boston Children's Hospital/Harvard Medical School and is currently completing her fellowship training in pediatric infectious diseases at the Children's Hospital of Philadelphia (CHOP), with the plan to transition to faculty at the University of California San Diego (UCSD) in 2020. The candidate's goals are to develop and refine the essential skills that will be required for a successful career as an independent investigator. The candidate specifically seeks to gain expertise in murine models of infection, bacterial genetics, genomics and advanced fluorescence microscopy to augment her research skills in immunology. Her long-term goal is to investigate and develop immune based treatment and therapeutic strategies to improve treatment paradigms and clinical outcomes for patients with highly drug-resistant infections. The mentor for this award is Professor Victor Nizet, an eminent physician-scientist and established leader in junior faculty development, innate immunology and experimental therapeutics. To add depth and breadth to the scientific and career guidance of the applicant, a Mentoring Committee is composed of scientists and physician- scientists from diverse and complementary fields. Dr. Ulloa will also benefit from the unparalleled resources and the unique, interdisciplinary working groups at UCSD including the Center for Immunity, Infection & Inflammation; the Center for Drug Discovery and Innovation; and the Collaborative to Halt Antibiotic-Resistant Microbes. The applicant's proposal is relevant to the U.S. National Action Plan to combat the increasing prevalence of drug-resistant pathogens that threaten our ability to manage life-threatening bacterial infections, and that pose significant challenges in balancing the efficacy and toxicity of potential antibiotic therapies. A solution proposed herein is to repurpose drugs that increase the antibacterial efficiency of important innate immune components. The foundation for this proposal is based on the candidate's first-author manuscript that describes how multidrug- resistant bacteria are sensitized to killing by the innate immune system in the presence of β-lactamase inhibitors, despite prevailing logic predicting this monotherapy to be fruitless. The mechanisms for such synergy and its therapeutic potential in vivo remain to be elucidated. The aims of this proposal are 1) to identify the mechanistic basis for β-lactamase inhibitor and antimicrobial peptide synergy, and 2) to investigate the therapeutic impact of β-lactamase inhibitors in vivo. These studies will provide a rationale for repurposing certain FDA-approved drugs, with known safety and tolerability, as adjunctive immunotherapies for the treatment of drug-resistant infections.

项目概要拟议的五年培训计划的目标是支持申请人独立性的发展作为一名儿科传染病学术医生，他的研究生涯专注于针对宿主的治疗申请人在斯坦福大学医学院完成了医学院学业。在波士顿儿童医院/哈佛医学院接受医学、儿科住院医师培训，目前正在她在费城儿童医院完成了儿科传染病的进修培训 (CHOP)，计划于 2020 年转任加州大学圣地亚哥分校 (UCSD) 教师。候选人的目标是发展和完善作为成功职业生涯所需的基本技能独立研究者特别寻求获得小鼠感染模型的专业知识，细菌遗传学、基因组学和先进的荧光显微镜，以增强她的研究技能她的长期目标是研究和开发基于免疫的治疗方法。改善高度耐药感染患者的治疗模式和临床结果的策略。该奖项的导师是维克多·尼泽 (Victor Nizet) 教授，他是一位杰出的医师科学家，也是医学界公认的领导者。初级教师发展、先天免疫学和治疗实验增加深度和广度。申请人的科学和职业指导，指导委员会由科学家和医生组成来自不同和互补领域的科学家也将受益于无与伦比的资源和加州大学圣地亚哥分校独特的跨学科工作组，包括免疫、感染和炎症中心；药物发现和创新中心；以及遏制抗生素耐药微生物合作组织。申请人的提案与美国打击日益流行的国家行动计划相关耐药病原体威胁我们处理危及生命的细菌感染的能力，并构成提出了平衡潜在抗生素疗法的功效和毒性的重大挑战。本文的目的是重新调整药物的用途，以提高重要先天免疫成分的抗菌效率。该提案的基础是基于候选人的第一作者手稿，该手稿描述了多种药物如何在 β-内酰胺酶抑制剂存在的情况下，耐药细菌会被先天免疫系统敏感地杀死，尽管普遍的逻辑预测这种单一疗法是徒劳的，但这种协同作用的机制及其作用。体内治疗潜力仍有待阐明该提案的目的是 1) 确定其机制。 β-内酰胺酶抑制剂和抗菌肽协同作用的基础，以及2）研究治疗影响这些研究将为重新利用某些 FDA 批准的药物提供依据。具有已知的安全性和耐受性，作为治疗耐药感染的辅助免疫疗法。