Role of amino acids and GTP in Staphylococcus aureus pathogenesis

氨基酸和 GTP 在金黄色葡萄球菌发病机制中的作用

基本信息

批准号：
9244962
负责人：
Shaun R Brinsmade
金额：
$ 23.33万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-09 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9244962
关键词：
Abscess Academic Medical Centers Affect Amino Acids Amoxicillin Anatomy Anterior Antibiotics Attenuated Bacteria Branched-Chain Amino Acids Child Clinical Communicable Diseases Communities Community-Acquired Infections DNA-Binding Proteins Dangerousness Data Development Disease Disease Progression Drops Emergency department visit Endocarditis Engineering Environment Epithelium Fluorescence Gene Expression Gene Expression Regulation Genes Genetic Transcription Genus staphylococcus Goals Growth Guanine Nucleotides Guanosine Triphosphate Health Hospitals Human Image In Vitro Individual Infection Infectious Agent Injection of therapeutic agent Isoleucine Laboratory culture Leucine Link Location Magnetic Resonance Imaging Measures Mediating Metabolism Modeling Mus Nutrient Organ Organism Osteomyelitis Pathogenesis Pathogenicity Patient risk Pharmaceutical Preparations Physiological Physiology Pneumonia Population Population Density Production Purine Nucleosides Regulation Reporter Repression Resistance Resolution Role Signal Transduction Site Skin Tissue Soft Tissue Infections Staphylococcus aureus Symbiosis Systemic infection Testing Therapeutic Time Tissues Toxin United States National Institutes of Health Valine Vancomycin Virulence Virulence Factors Virulent Work analog commensal microbes derepression design exhaust gene product genetic regulatory protein imaging modality in vivo interest killings methicillin resistant Staphylococcus aureus mutant novel therapeutic intervention novel therapeutics overexpression pathogen pre-clinical prevent ratiometric response therapeutic target tool

项目摘要

7. Project Summary/Abstract. Staphylococcus aureus colonizes 30-50% of the population and is the leading cause of skin and soft tissue infections, osteomyelitis, pneumonia and endocarditis. At a time when hospital-acquired staphylococcal disease is decreasing, particularly dangerous clones of S. aureus pose a major health threat to otherwise healthy individuals, especially children. These community-acquired (CA) infections are the most frequent cause of emergency room visits and are resistant to a number of first- and last-line antibiotics (for example, amoxicillin and vancomycin). The use and misuse of these antibiotics promotes the rise of resistance by selecting for growth; therefore it is preferable to disable the ability to cause disease than to kill the bacteria. Previous work has shown that the S. aureus regulatory protein CodY helps to suppress the production of virulence factors when activated by the amino acids isoleucine, leucine and valine (ILV), and guanosine triphosphate (GTP). In the absence of active CodY and suppression, toxins and other disease-causing factors are elevated and those bacteria are significantly more virulent. Moreover, maintaining activity during growth keeps CodY-dependent genes repressed. Therefore, CodY could be exploited as an anti-virulence therapy and allow at-risk patients to clear the infection naturally. Before doing so, it is essential to establish that CodY activity changes within tissues during infection. If so, administering analogs of ILV and guanine nucleotides that prevent loss of CodY activity could potentially prevent staphylococcal disease. In this proposal we seek to do two things to reveal the relationship between CodY, host nutrients, and regulation of gene expression: i.) assess whether host tissue affects CodY-dependent gene expression using cutting edge in vivo and ex vivo live imaging and fluorescent reporters, and ii.) determine whether increasing ILV abundance in staphylococci during infection affects pathogenicity. We will collaborate with CA-staphylococcal biologist Michael Otto (National Institutes of Health), and preclinical imaging experts led by Christopher Albanese (Georgetown University Medical Center). Together, we will employ a multifaceted approach to gain a deeper understanding of CodY function in vivo and to test this anti-virulence approach.

7. 项目总结/摘要。金黄色葡萄球菌占人口的 30-50%，是皮肤和软组织感染的主要原因感染、骨髓炎、肺炎和心内膜炎。当医院获得性葡萄球菌疾病正在减少，特别危险的金黄色葡萄球菌克隆对其他人构成重大健康威胁健康人，尤其是儿童。这些社区获得性 (CA) 感染是最常见的原因急诊室就诊的次数，并且对许多一线和末线抗生素（例如，阿莫西林和万古霉素）。这些抗生素的使用和滥用会通过以下方式促进耐药性的增加选择成长；因此，最好是使其丧失致病能力，而不是杀死细菌。先前的研究表明，金黄色葡萄球菌调节蛋白 CodY 有助于抑制被氨基酸异亮氨酸、亮氨酸和缬氨酸 (ILV) 以及鸟苷激活时的毒力因子三磷酸（GTP）。在缺乏活性 CodY 和抑制、毒素和其他致病因素的情况下升高，这些细菌的毒性明显增强。此外，在生长过程中保持活性抑制 CodY 依赖性基因。因此，CodY 可用作抗毒力疗法让高危患者自然清除感染。在此之前，必须先确定 CodY 感染期间组织内的活性发生变化。如果是这样，则施用 ILV 和鸟嘌呤核苷酸的类似物防止 CodY 活性丧失可能会预防葡萄球菌疾病。在本提案中，我们力求做到揭示 CodY、宿主营养物质和基因表达调控之间关系的两件事：i.) 使用体内和离体尖端技术评估宿主组织是否影响 CodY 依赖性基因表达实时成像和荧光报告基因，ii.) 确定葡萄球菌中 ILV 丰度是否增加感染期间影响致病性。我们将与 CA-葡萄球菌生物学家 Michael Otto 合作（美国国立卫生研究院）和 Christopher Albanese（乔治敦）领导的临床前成像专家大学医学中心）。我们将共同采用多方面的方法来获得更深入的了解 CodY 在体内的功能并测试这种抗毒力方法。