Attacking the Global Problem of Antimicrobial Resistance

解决全球抗生素耐药性问题

基本信息

批准号：
10477990
负责人：
LINDA D HAZLETT
金额：
$ 37.35万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-01-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10477990
关键词：
Accidents Affect Animal Model Antibiotic Therapy Antibiotics Antimicrobial Effect Antimicrobial Resistance Bacteria Bacterial Infections Bacterial Outer Membrane Proteins Binding Blindness Brain Injuries C57BL/6 Mouse Cell Maturation Cell Nucleus Cell surface Cells Chromatin Chronic Hepatitis Ciprofloxacin Clinical Clinical Management Colitis Contact Lenses Cornea Corneal Diseases Cytoplasm Data Deltastab Dendritic Cells Developed Countries Disease Drug resistance Effectiveness Excision Eye Infections Eye Injuries Family Genes Glycyrrhiza Glycyrrhizic Acid HMGB1 Protein Healthcare Systems Immune Immune response Immunologic Receptors Infection Inflammatory Inflammatory Response Keratitis Knockout Mice Knowledge Licorice Lipopolysaccharides Mediating Membrane Molecular Morphology Moxifloxacin Multi-Drug Resistance Mus Myelogenous Myeloid Cells Nerve Neutrophil Infiltration Neutrophilic Infiltrate Organism Pattern Physiologic Intraocular Pressure Physiological Plant Roots Post-Translational Protein Processing Prevention Process Production Proteins Pseudomonas aeruginosa Pseudomonas aeruginosa infection Publishing Recommendation Resistance Sepsis Signal Pathway Signal Transduction TLR4 gene Testing VDAC1 gene antimicrobial bacterial resistance chemokine conjunctiva cost cytokine economic impact efflux pump emerging antibiotic resistance extracellular health care economics healthcare-associated infections in vivo lung injury macrophage member multidrug-resistant Pseudomonas aeruginosa novel therapeutics opportunistic pathogen overexpression prevent programs protective effect receptor for advanced glycation endproducts translational study

项目摘要

Project Summary Besides the impact on health care, the economic impact of antimicrobial resistance is significant. More than two million infections a year are caused by bacteria that are resistant to at least first-line antibiotics, costing the US health care system 20 billion dollars each year. Pseudomonas aeruginosa (PA) causes over 51,000 health care associated infections per year in the US, of which 13% are multi-drug resistant (MDR). Non-antibiotic approaches to prevent and treat bacterial infections provide attractive alternatives/adjuncts to antibiotics no longer effective against MDR PA isolates. One of these, glycyrrhizin (GLY), an extract from the licorice root (Glycyrrhiza glabra), is effective in treatment of animal models of sepsis, colitis, lung and brain injury; and is used in the clinical management of chronic hepatitis. After infection, GLY reduces extracellularly released high mobility group box 1 (HMGB1), a prototypic alarmin that activates cell surface innate immune receptors affecting host inflammatory responses. GLY has direct antimicrobial effects in PA experimental keratitis induced by non-MDR clinical (keratitis) isolates (e.g., KEI 1025) and by MDR9, a non-ocular isolate. Preliminary/recently published data support that in MDR9 induced PA keratitis, GLY: a) permeabilizes bacterial membranes, b) reduces efflux pump activity, increases bacterial killing and d) combined with Ciprofloxacin in vivo, reduces the neutrophil infiltrate and plate count optimally. Therefore, our overarching hypothesis is that GLY is non-toxic to the cornea and ocular adnexa and after PA infection, binds to HMGB1 preventing activation of innate immune receptors. To test this hypothesis two Specific aims are proposed. Specific Aim 1: Tests the hypothesis that GLY is well-tolerated and does not alter the cytoarchitectue nor the physiological parameters of the normal cornea, conjunctiva and ocular adnexa. In this aim, we will test the effects of GLY given topically on the uninfected, normal cornea, and if intraocular pressure (IOP), tear volume, corneal nerve pattern, corneal sensitivity, resident immune cells and/or conjunctiva are altered. Specific Aim 2: Tests the hypothesis that GLY's protective effect on PA keratitis is mediated by inhibiting HMGB1 amplification of TLR4/RAGE signaling pathways in myeloid cells. This aim will test if GLY binding to HMGB1, inhibits HMGB1-TLR4 (-RAGE) interactions and signaling pathways, with downstream effects on immature myeloid dendritic cell (DC) maturation, macrophage production of proinflammatory cytokines and chemokines and neutrophil infiltration and function. Aim 2a will test this hypothesis in GLY treated mice after infection with KEI1025, a non-MDR PA keratitis isolate using TLR4 and RAGE KO mice and myeloid specific HMGB1 KO mice. Aim 2b is translational and will test this hypothesis in mice in which GLY treatment is combined with Moxifloxacin and initiated 18h after infection with MDR PA.

项目概要除了对医疗保健的影响之外，抗菌素耐药性的经济影响也很显着。多于每年有 200 万例感染是由至少对一线抗生素具有抗药性的细菌引起的，美国医疗保健系统每年200亿美元。铜绿假单胞菌 (PA) 导致超过 51,000 人健康美国每年都会发生与护理相关的感染，其中 13% 具有多重耐药性 (MDR)。非抗生素预防和治疗细菌感染的方法为抗生素提供了有吸引力的替代品/辅助品否对 MDR PA 分离株更有效。其中之一是甘草酸 (GLY)，一种从甘草根中提取的物质（光果甘草）可有效治疗败血症、结肠炎、肺和脑损伤的动物模型；并且是用于慢性肝炎的临床治疗。感染后，GLY 减少细胞外释放的高浓度移动组盒 1 (HMGB1)，一种激活细胞表面先天免疫受体的原型警报素影响宿主炎症反应。 GLY 对 PA 实验性角膜炎具有直接抗菌作用由非 MDR 临床（角膜炎）分离株（例如 KEI 1025）和 MDR9（一种非眼部分离株）诱导。初步/最近发表的数据支持在 MDR9 诱导的 PA 角膜炎中，GLY：a) 使细菌透化膜，b) 降低外排泵活性，增加细菌杀灭率，d) 与环丙沙星联合使用体内，最佳地减少中性粒细胞浸润和平板计数。因此，我们的总体假设是 GLY 对角膜和眼附件无毒，PA 感染后，与 HMGB1 结合，防止先天免疫受体的激活。为了检验这一假设，提出了两个具体目标。具体目标 1：检验 GLY 耐受性良好且不会改变细胞结构或细胞结构的假设正常角膜、结膜和眼附件的生理参数。为了这个目标，我们将测试局部给予 GLY 对未感染的正常角膜的影响，以及眼压 (IOP)、泪液量、角膜神经模式、角膜敏感性、驻留免疫细胞和/或结膜发生改变。具体目标 2：检验 GLY 对 PA 角膜炎的保护作用是通过抑制介导的假设骨髓细胞中 TLR4/RAGE 信号通路的 HMGB1 放大。该目的将测试 GLY 是否与 HMGB1，抑制 HMGB1-TLR4 (-RAGE) 相互作用和信号通路，并对下游产生影响未成熟的骨髓树突状细胞 (DC) 成熟、巨噬细胞产生促炎细胞因子和趋化因子和中性粒细胞浸润和功能。目标 2a 将在 GLY 处理的小鼠中检验这一假设使用 TLR4 和 RAGE KO 小鼠和骨髓特异性感染 KEI1025（一种非 MDR PA 角膜炎分离株） HMGB1 KO 小鼠。目标 2b 是转化性的，将在接受 GLY 治疗的小鼠中检验这一假设。与莫西沙星联合使用，并在感染MDR PA后18小时开始。