The role of arginine catabolic pathways in modulating staphylococcal fitness

精氨酸分解代谢途径在调节葡萄球菌适应性中的作用

基本信息

批准号：
10053306
负责人：
Vinai Chittezham Thomas
金额：
$ 37.63万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-11-06 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10053306
关键词：
Acetates Acids Address Adhesions Affect Anabolism Antibiotic Resistance Apoptosis Arginine Arginine deiminase Bacterial Adhesins Biochemical Biological Biology Carbon Catheters Cell Death Cells Chemosensitization Citric Acid Cycle Citrulline Coagulase Cytochromes Cytoplasm Data Deaminase Defect Development Environment Enzymes Extravasation Future Genetic Genus staphylococcus Glutamates Goals Growth Heme Homeostasis Hospitals Human Hydro-Lyases Incidence Infant Infection Intervention Investigation Link Maintenance Mediating Metabolic Metabolic Pathway Metabolic dysfunction Metabolism Microbial Biofilms Modeling Mutation Analysis NADP Neuraxis Nitric Oxide Nitric Oxide Synthase Nitrites Operon Oxidases Oxidation-Reduction Oxidative Stress Pathogenesis Pathogenicity Pathology Pathway interactions Peptidoglycan Phase Phenotype Phenylalanine Physiological Physiology Play Polysaccharides Process Production Prokaryotic Cells Proteins Public Health Pyruvate Reactive Oxygen Species Resistance Resources Respiration Role Source Staphylococcal Infections Staphylococcus aureus Staphylococcus epidermidis Sulfite reductase Superoxides Testing Therapeutic Therapeutic Intervention Time arginase base catalase clinical care design electron donor experimental study fitness glucose metabolism growth promoting activity insight mouse model mutant new therapeutic target novel therapeutics oxidation pathogen pathogenic bacteria prevent targeted treatment therapeutically effective

项目摘要

ABSTRACT Despite decades of advances in clinical care, the high incidence of staphylococcal infections remain a major public health concern. Multiple antibiotic-resistant isolates of Staphylococcus aureus and coagulase-negative Staphylococcus epidermidis are frequently isolated in the hospital environment and significantly limit therapeutic options. Indeed, it is increasingly becoming evident that a fundamental understanding of staphylococcal biology and factors affecting its fitness are required for the development of effective therapeutics. Towards this goal, we have recently identified important physiological functions for arginine catabolic enzymes including nitric oxide synthase (NOS) and arginine deiminase (ADI), in promoting growth and controlling programmed cell death (PCD) in staphylococci. Under normal physiological conditions, NOS activity promotes growth by activating respiration and preventing metabolic dysfunction including excessive production of the polysaccharide intracellular adhesin (PIA). However, influx of acetate (a byproduct of glucose metabolism) into the cytoplasm under acidic conditions appears to corrupt normal function of NOS and promotes NOS-dependent production of reactive oxygen species (ROS) and PCD. Interestingly, carbon flux through the ADI pathway appears to counter NOS-dependent PCD. The mechanism by which these pathways affect staphylococcal physiology is still under intense investigation and constitutes the subject of this application. In Aim #1, we will test how NOS promotes growth by suppressing PIA production as part of its normal physiological activity. Further, we will investigate if phenylalanine plays a role in NOS-dependent PIA suppression and whether NOS activity affects the pathogenic potential of staphylococci using an infant mouse model of central nervous system (CNS) catheter infection. In Aim #2, we will test the hypothesis that NOS-dependent ROS production during PCD results from NOS uncoupling, a phenomenon wherein NOS generates superoxide rather than nitric oxide as byproduct. Finally in Aim #3, we will test the potential for the arginine deiminase and the arginase pathways in countering PCD by activating catalase activity through glutamate biosynthesis. On completion of these studies, we will gain a deeper mechanistic understanding of how various arginine catabolic pathways affect staphylococcal physiology and fitness.

抽象的尽管临床护理取得了数十年的进步，葡萄球菌感染的高发病率仍然是一个主要问题公共卫生问题。多重耐药金黄色葡萄球菌和凝固酶阴性分离株表皮葡萄球菌经常在医院环境中分离出来，严重限制了治疗选项。事实上，越来越明显的是，对葡萄球菌生物学的基本了解开发有效的治疗方法需要影响其适应性的因素。为了这个目标，我们最近发现了精氨酸分解代谢酶的重要生理功能，包括一氧化氮合成酶 (NOS) 和精氨酸脱亚胺酶 (ADI)，促进生长和控制程序性细胞死亡 (PCD) 在葡萄球菌中。在正常生理条件下，NOS活性通过激活呼吸促进生长并预防代谢功能障碍，包括多糖细胞内粘附素的过度产生（PIA）。然而，在酸性条件下，乙酸盐（葡萄糖代谢的副产品）流入细胞质似乎会破坏 NOS 的正常功能并促进 NOS 依赖性活性氧的产生（ROS）和 PCD。有趣的是，通过 ADI 途径的碳通量似乎可以抵消 NOS 依赖性 PCD。这些途径影响葡萄球菌生理学的机制仍在深入研究中并构成本申请的主题。在目标 1 中，我们将测试 NOS 如何通过抑制来促进生长 PIA 的产生是其正常生理活动的一部分。此外，我们将研究苯丙氨酸是否发挥作用 NOS 依赖性 PIA 抑制中的作用以及 NOS 活性是否影响致病潜力使用中枢神经系统（CNS）导管感染的幼年小鼠模型来检测葡萄球菌。在目标#2中，我们将检验 PCD 期间 NOS 依赖性 ROS 产生是由 NOS 解偶联导致的假设， NOS 产生超氧化物而不是一氧化氮作为副产物的现象。最后，在目标#3中，我们将测试精氨酸脱亚胺酶和精氨酸酶途径通过激活过氧化氢酶对抗 PCD 的潜力通过谷氨酸生物合成的活性。完成这些研究后，我们将获得更深入的机制了解各种精氨酸分解代谢途径如何影响葡萄球菌的生理和健康。