The Molecular Control of Cell Death in Staphylococcus aureus

金黄色葡萄球菌细胞死亡的分子控制

• 批准号: 7915540
• 负责人: Jeffrey Lee Bose
• 金额: $ 5.05万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915540
• 关键词: Anti-Bacterial Agents; Antibiotic Therapy; Antibiotics; Apoptosis; Archaea; Autolysis; Bacteria; Bacterial Infections; Bacteriophages; Biological Assay; Cell Death; Cell Survival; Cell Wall; Cells; Communities; Complex; Cytolysis; Development; Developmental Process; Environment; Exhibits; Genes; Genetic Transcription; Goals; Growth; Health; Human; Immune system; Infection; Lead; Learning; Mechanics; Microbial Biofilms; Molecular; Mutation; N-Acetylmuramoyl-L-alanine Amidase; Operon; Phenotype; Play; Process; Production; Proteins; Research; Role; Staphylococcus aureus; Testing; Therapeutic; Western Blotting; Work; base; clinically significant; combat; genome sequencing; insight; mutant; novel; pathogen; protein protein interaction; public health relevance; research study

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand how bacterial autolysis contributes to biofilm formation. Bacteria are commonly found in the environment as complex biofilm communities. This has clinical significance as pathogens often form biofilms during infection and protect the pathogen from the immune system and antibiotics. Recently, controlled cell death and lysis modulated by the cidABC and IrgAB operons have been shown to be important in Staphylococcus aureus biofilm formation. In the current application, two of the proteins encoded in these operons, CidB and LrgB, will be examined. These proteins are wide-spread, being found in 46 percent of sequenced genomes including bacteria and archaea, yet none have a predicted or assigned function. The specific aims of this application are to: 1) characterize mutants in the genes encoding these proteins using assays of cell survival and autolysis, antibiotic tolerance, and biofilm production; and, 2) examine the cellular localization and protein-protein interactions that may be important for function. The results of the experiments outlined in this study will examine the function of two previously uncharacterized proteins believed to be involved in controlling cell death and lysis. This will provide insight into the poorly understood process of programmed cell death in bacteria and how this process contributes to the establishment of a biofilm. Finally, it may suggest new avenues to pursue for the development of novel antibacterial agents. PUBLIC HEALTH RELEVANCE: Bacterial infections are a growing threat to human health around the world primarily due to their increasing ability to cause infections recalcitrant to antibiotic therapy. The research described in this application focuses on the novel concept that bacteria regulate their own cell death as part of complex developmental processes. The results generated by these studies will provide a better understanding of the molecular mechanisms controlling bacterial cell death and will lead to novel and more effective therapeutic strategies to combat infections.

描述（由申请人提供）：本研究的长期目标是了解细菌自溶如何促进生物膜形成。细菌通常作为复杂的生物膜群落存在于环境中。这具有临床意义，因为病原体通常在感染期间形成生物膜，并保护病原体免受免疫系统和抗生素的侵害。最近，已显示出受控的细胞死亡和溶解调节的ERABC和IrgAB操纵子是重要的金黄色葡萄球菌生物膜的形成。在本申请中，将检查这些操纵子中编码的两种蛋白质CidB和LrgB。这些蛋白质分布广泛，存在于46%的测序基因组中，包括细菌和古细菌，但没有一个具有预测或指定的功能。本申请的具体目的是：1）使用细胞存活和自溶、抗生素耐受性和生物膜产生的测定来表征编码这些蛋白质的基因中的突变体;以及2）检查可能对功能重要的细胞定位和蛋白质-蛋白质相互作用。在这项研究中概述的实验结果将检查两个以前未知的蛋白质的功能，据信参与控制细胞死亡和裂解。这将提供深入了解细菌中程序性细胞死亡的过程以及该过程如何有助于建立生物膜。最后，它可能为新型抗菌剂的开发提供了新的途径。公共卫生相关性：细菌感染对全世界人类健康的威胁越来越大，主要是由于它们引起抗生素治疗无效的感染的能力不断增加。本申请中描述的研究集中在细菌调节自身细胞死亡作为复杂发育过程的一部分的新概念上。这些研究产生的结果将更好地了解控制细菌细胞死亡的分子机制，并将导致新的和更有效的治疗策略来对抗感染。