Staphylococcus aureus ribosomal protein processing, a potential new drug target

金黄色葡萄球菌核糖体蛋白加工，一个潜在的新药物靶点

• 批准号: 8768939
• 负责人: GAIL E CHRISTIE
• 金额: $ 18.43万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768939
• 关键词: Amino Acids; Animals; Antibiotic Resistance; Antibiotics; Appearance; Biochemical; Bioinformatics; Biological Assay; Cleaved cell; Communities; Community Hospitals; Development; Disease; Drug Targeting; Endocarditis; Event; Foundations; Genetic; Goals; Gram-Positive Bacteria; Growth; Health Hazards; Healthcare; Horizontal Gene Transfer; Hospitals; Human; Infection; Kinetics; Laboratories; Lead; Life; Medical Device; Minor; N-terminal; Osteomyelitis; Peptide Hydrolases; Peptides; Peptidyltransferase; Physiological; Pneumonia; Process; Production; Protease Inhibitor; Proteins; Public Health; Reaction; Research; Ribosomal Proteins; Ribosomes; Role; Skin Tissue; Soft Tissue Infections; Staging; Staphylococcus aureus; Substrate Specificity; Surgical wound; Testing; Toxic Shock Syndrome; Variant; Virulent; Work; antimicrobial; base; design; inhibitor/antagonist; novel; pathogen; pressure; public health priorities; public health relevance; resistant strain; screening; small molecule

DESCRIPTION (provided by applicant): Staphylococcus aureus is a versatile human pathogen that is responsible for both healthcare-associated infections and, increasingly, community acquired disease. S. aureus causes a wide range of diseases, from minor skin and soft tissue infections to more serious disorders including pneumonia, toxic shock, osteomyelitis and endocarditis. It is commonly found associated with infection of indwelling medical devices and surgical wounds. The emergence of aggressive strains resistant to multiple antibiotics, in combination with widespread horizontal gene transfer, poses a significant public health hazard. The ability of S. aureus to adapt rapidly to antibiotic pressure underscores the need for continued development of new targets for antimicrobial therapy. Recent work in our laboratory has led to the discovery that one of the proteins in the large subunit of the ribosome is subject t a specific N-terminal cleavage in S. aureus and other Gram positive bacteria. Several lines of evidence are consistent with the hypothesis that this cleavage event is essential. Bioinformatic and biochemical studies have led to the identification of the protease responsible for this cleavage. This proposal includes a combination of genetic and biochemical approaches to confirm the requirement for cleavage and the characterization of the protease. We will develop a cleavage assay and identify key amino acid residues in the protease and in the ribosomal protein that are necessary for this targeted cleavage event. These studies will elucidate the role of this novel ribosomal protein processing event and set the stage for subsequent efforts aimed at the development of a new class of antibiotics that will inhibit this cleavage reaction.

描述(由申请人提供)：金黄色葡萄球菌是一种多功能的人类病原体，它既导致与医疗保健相关的感染，也越来越多地导致社区获得性疾病。金黄色葡萄球菌引起多种疾病，从轻微的皮肤和软组织感染到更严重的疾病，包括肺炎、中毒性休克、骨髓炎和心内膜炎。它通常被发现与留置医疗器械和手术伤口的感染有关。对多种抗生素产生抗药性的侵袭性菌株的出现，再加上广泛的水平基因转移，构成了重大的公共卫生危害。金黄色葡萄球菌对抗生素压力的快速适应能力突显了继续开发新的抗菌治疗靶点的必要性。我们实验室最近的工作发现，在金黄色葡萄球菌和其他革兰氏阳性细菌中，核糖体大亚基中的一种蛋白质受到特定的N端切割。有几条证据与这一卵裂事件至关重要的假设相一致。生物信息学和生化研究已经导致了对这种切割负责的蛋白酶的鉴定。这一建议包括结合遗传和生化方法来确认对切割的要求和对蛋白酶的特性。我们将开发一种切割试验，并确定蛋白酶和核糖体蛋白中的关键氨基酸残基，这些氨基酸残基是这一靶向切割事件所必需的。这些研究将阐明这一新颖的核糖体蛋白质加工事件的作用，并为随后旨在开发抑制这种切割反应的新型抗生素的努力奠定基础。