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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.

摘要