The Molecular Control of Cell Death in Staphylococcus aureus

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的形成。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，因为病原体在感染过程中经常形成生物膜，保护病原体免受免疫系统和抗生素的侵害。近年来，cidABC和IrgAB操纵子调控的细胞死亡和裂解在金黄色葡萄球菌生物膜形成中起重要作用。在目前的应用中，将对这些操作子中编码的两种蛋白质CidB和LrgB进行研究。这些蛋白质分布广泛，在46%的测序基因组中发现，包括细菌和古细菌，但没有一个具有预测或指定的功能。该应用程序的具体目的是：1)利用细胞存活和自溶、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突变；2)检查细胞定位和蛋白质-蛋白质相互作用，这可能对功能很重要。本研究中概述的实验结果将检查两个先前未表征的蛋白质的功能，这些蛋白质被认为参与控制细胞死亡和裂解。这将有助于深入了解细菌程序性细胞死亡的过程，以及这一过程如何有助于建立生物膜。最后，这可能为开发新型抗菌剂提供新的途径。公共卫生相关性：细菌感染在世界各地对人类健康的威胁日益严重，主要是因为它们引起抗生素治疗难以抵抗的感染的能力日益增强。在本应用程序中描述的研究侧重于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。这些研究产生的结果将更好地理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。

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.