Inducible Antibiotic Resistance in Methicillin-Resistant Staphylococcus aureus

耐甲氧西林金黄色葡萄球菌诱导的抗生素耐药性

• 批准号: 10083692
• 负责人: Shahriar Mobashery
• 金额: $ 51.86万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083692
• 关键词: Acylation; Address; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Applications Grants; Back; Binding; Binding Proteins; Biochemical; Complex; Cytoplasm; Cytoplasmic Tail; Data; Decarboxylation; Event; Exhibits; Exposure to; Genes; Genetic Transcription; Human; In Vitro; Intervention; Lead; Light; Link; Lysine; Membrane; Membrane Proteins; Monobactams; Organism; Penicillin-Binding Proteins; Peptide Hydrolases; Pharmacology; Phenotype; Phosphorylation; Prevention; Property; Protease Domain; Proteins; Proteolysis; Resistance; Serine; Side; Signal Transduction; Site; Staphylococcus aureus infection; Structure-Activity Relationship; Surface; System; Time; Transducers; Work; beta-Lactam Resistance; beta-Lactamase; beta-Lactams; experience; experimental study; human pathogen; in vivo; inhibitor/antagonist; methicillin resistant Staphylococcus aureus; pathogenic bacteria; prevent; response; sensor; small molecule; trait

Project Summary/Abstract Methicillin-resistant Staphylococcus aureus (MRSA) is a problematic human bacterial pathogen, which is broadly resistant to β-lactam antibiotics. This resistance is inducible and is conferred by a set of genes that encode an antibiotic sensor/signal transducer protein, a gene repressor and two resistance determinants (a class A β-lactamases and a unique penicillin-binding protein (PBP) designated as PBP2a). Covalent binding of the β-lactam antibiotic to the surface domain of the sensor/signal transducer protein initiates the induction of resistance, which entails biochemical events on the cytoplasmic side involving proteolysis of the gene repressor and transcription of the genes for the antibiotic-resistance determinants. We address the sequence of events that take place in the cytoplasm in this grant application. We propose in Specific Aim 1 to study two responses that MRSA experiences after the recognition of the antibiotic on the surface. One is a fragmentation of the BlaR1 (the sensor/transducer protein) in its cytoplasmic protease domain, which is believed to activate it (i.e., bring it out of latency). Another is phosphorylation of a protein that we refer to as BlaR2. We propose to document that proteolysis of the cytoplasmic domain initiates the onset of induction. Phosphorylation of BlaR2 also ensues antibiotic recognition on the surface and is essential for the antibiotic response. We propose to identify and characterize BlaR2 and determine the site of its phosphorylation in elucidating a functional link between activation of BlaR1 and phosphorylation of BlaR2. In Specific Aim 2, we would like to build on our preliminary findings on inhibitors of BlaR2 phosphorylation in identification of molecules that could serve as potentiators of β-lactam antibiotics. This class of compounds prevents BlaR2 phosphorylation, which we have documented to result in sensitization of the organism to β-lactam antibiotics. Such a class of molecules has the potential of bring back β-lactam antibiotics from obsolescence in treatment of MRSA infections. MRSA has been with humanity for over 50 years. These studies will shed definitive light on the complex machinery that MRSA strains have evolved for resistance to β-lactam antibiotics.

项目摘要/摘要 耐甲氧西林金黄色葡萄球菌(MRSA)是一种有问题的人类细菌病原体，它是 对β-内酰胺类抗生素广泛耐药。这种抗性是可诱导的，并由一组基因授予 编码抗生素传感器/信号转导蛋白、基因抑制子和两个耐药决定簇(a A类β-内酰胺酶和一种独特的青霉素结合蛋白(命名为PBP2a)。的共价结合 β-内酰胺类抗生素对传感器/信号转导蛋白表面域的诱导作用 抗性，这需要细胞质方面的生化事件，涉及基因的蛋白分解 抗生素耐药决定基因的抑制和转录。我们解决了序列问题 在这项拨款申请中发生在细胞质中的事件。我们在具体目标1中建议研究两个 耐甲氧西林金黄色葡萄球菌在表面识别抗生素后的反应。一个是碎片化 BlaR1(传感器/转导蛋白)在其细胞质蛋白酶域中的表达，据信可以激活它 (即，让它走出延迟)。另一种是蛋白质的磷酸化，我们称之为BlaR2。我们建议 证明胞浆结构域的蛋白分解启动了诱导的开始。BlaR2的磷酸化 还会在表面上识别抗生素，并对抗生素反应至关重要。我们建议 鉴定和鉴定BlaR2并确定其在阐明功能连接时的磷酸化位置 BlaR1的激活和BlaR2的磷酸化之间的关系。在具体目标2中，我们希望在我们的基础上 BlaR2磷酸化抑制剂在鉴定可作为 β-内酰胺类抗生素的增效剂。这类化合物阻止BlaR2的磷酸化，我们有 记录导致有机体对β-内酰胺类抗生素敏感。这样一类分子具有 恢复β-内酰胺类抗生素在治疗耐甲氧西林金黄色葡萄球菌感染中的潜力。MRSA已经 已经和人类在一起50多年了。这些研究将最终阐明复杂的机械 耐甲氧西林金黄色葡萄球菌菌株已经进化出对β-内酰胺类抗生素的耐药性。