The role of GraRS in resistance to cationic antimicrobial peptides in S. aureus

GraRS 在金黄色葡萄球菌对阳离子抗菌肽耐药中的作用

基本信息

批准号：
8770008
负责人：
Ambrose Lin Yau Cheung
金额：
$ 48.7万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8770008
关键词：
ATP phosphohydrolase ATP-Binding Cassette Transporters Alanine Anatomy Animals Antibiotic Resistance Antibiotics Antimicrobial Cationic Peptides Area Bacteremia Bacteria Binding Blood Circulation Blood Platelets Body Fluids Charge Communities Community Hospitals Complement Cyclic Peptides Daptomycin Development Endocarditis Event Exposure to Focal Infection Future Genes Genetic Genome Goals HMGN Proteins Health Host Defense Human Indium Individual Infection Infectious Skin Diseases Infective endocarditis Integration Host Factors Length Life Link Lysine Mediating Membrane Membrane Biology Microarray Analysis Modeling Molecular Molecular Genetics Mutation Natural Immunity Operon Organism Oryctolagus cuniculus Outcome Oxacillin Pathogenesis Patients Peptides Phospholipids Phosphotransferases Play Polymyxin Resistance Predisposition Proteins Research Resistance Resistance development Risk Role Source Staphylococcus aureus Stimulus Structure Structure-Activity Relationship Surface System Teichoic Acids Tissues Vancomycin Vancomycin-resistant S. aureus Virulence Virulent antimicrobial antimicrobial peptide base design epimerase extracellular in vivo indolicidin interest killings methicillin resistant Staphylococcus aureus neutrophil pathogen peptide structure permease resistance mechanism response sensor skills sugar

项目摘要

DESCRIPTION (provided by applicant): S. aureus is a highly adaptive human pathogen. One result of this adaptation is its ability to develop resistance cationic antimicrobial peptides (CAPs), which are an important part of innate immunity in the hosts. In perusing the S. aureus genomes, we found four two component regulatory systems each of lie adjacent to an ABC transporter system. One of the system, GraRS, regulates the adjacent VraFG efflux system comprising an ATPase and a membrane permease. Mutations in graR or vraG have led to a reduction in resistance to CAPs such as RP-1 (a congener to PMP-1 from platelets) and hNP-1 (from neutrophils), indolicidin and LL37. As an intravascular pathogen, S. aureus likely encounters CAPs from platelets and neutrophils (RP-1 and hNP-1), which we will focus on in this proposal. The exposure of S. aureus to selective CAP has also led to induction of graRS and vraFG and other genes relevant CAP resistance including mprF, dltABCD and also another set of ABC transporter genes vraDE, based on induction studies and microarray analysis. However, the exact contribution of these genes to CAP resistance mediated by GraRS in S. aureus is not defined (Aim I). In addition, in contrast to S. epidermidis where the expression of graRS and vraFG can be induced by any CAPs, the induction in S. aureus is more selective, responding to only a few CAPs. Based on the difference in the sequence of the kinase sensor GraS between S. aureus and S. epidermidis, we propose to define the exact residues within GraS that mediate this recognition of specific CAPs for induction of downstream genes (Aim II). Besides the bacterial factors, we are also interested in the structure of synthetic CAPs and their ability to bind and induce expression of graRS (Aim III). Finally, the in vivo correlate of these finding in GraRS will be explored in a relevant rabbit model of infective endocarditis. Together, these studies will elicit the scientific basis of innate resistance to relevant host CAPs in S. aureus, thus providing a platform to devise strategies to alleviate resistance to cationic antimicrobial peptides.

描述（由申请人提供）：金黄色葡萄球菌是一种高度适应性的人类病原体。这种适应的结果之一是它能够产生抗性阳离子抗菌肽（CAP），这是宿主先天免疫的重要组成部分。在仔细研究金黄色葡萄球菌基因组时，我们发现了四个两部分调节系统，每个调节系统都与 ABC 转运系统相邻。其中一个系统 GraRS 调节相邻的 VraFG 流出系统，该系统包括 ATP 酶和膜通透酶。 graR 或 vraG 突变导致对 CAP 的耐药性降低，例如 RP-1（血小板中 PMP-1 的同源物）和 hNP-1（中性粒细胞中的）、indolicidin 和 LL37。作为一种血管内病原体，金黄色葡萄球菌可能会遇到来自血小板和中性粒细胞（RP-1 和 hNP-1）的 CAP，我们将在本提案中重点关注。根据诱导研究和微阵列分析，金黄色葡萄球菌暴露于选择性 CAP 还导致诱导 graRS 和 vraFG 以及其他与 CAP 抗性相关的基因，包括 mprF、dltABCD 以及另一组 ABC 转运蛋白基因 vraDE。然而，这些基因对金黄色葡萄球菌中 GraRS 介导的 CAP 抗性的确切贡献尚未确定（目标 I）。此外，与表皮葡萄球菌中任何 CAP 都可以诱导 graRS 和 vraFG 的表达相比，金黄色葡萄球菌中的诱导更具选择性，仅对少数 CAP 做出反应。基于金黄色葡萄球菌和表皮葡萄球菌激酶传感器 GraS 序列的差异，我们建议定义 GraS 中介导特定 CAP 识别以诱导下游基因的确切残基（目标 II）。除了细菌因素外，我们还对合成 CAP 的结构及其结合和诱导 graRS 表达的能力感兴趣（目标 III）。最后，将在相关的感染性心内膜炎兔模型中探索 GraRS 中这些发现的体内相关性。总之，这些研究将得出金黄色葡萄球菌对相关宿主 CAP 的先天耐药性的科学依据，从而提供一个平台来制定减轻对阳离子抗菌肽耐药性的策略。