A Novel Essential Regulator of Staphylococcus aureus

描述(申请人提供)：金黄色葡萄球菌是一种主要的社区和医院获得性病原体，在世界范围内引起皮肤表浅和危及生命的感染。金黄色葡萄球菌多重耐药菌株的不断出现，特别是甲氧西林和万古霉素中间耐药菌株的出现，是一个重大的公共卫生问题。这种生物已经进化成一系列的双组分信号转导系统(TCS)，以感知其周围环境，调节细胞反应和毒力基因的表达。我们的长期目标是阐明控制关键途径基因表达的调控机制，以确定有效预防和/或治疗金黄色葡萄球菌的新靶点。具体的假设是，一种新的金黄色葡萄球菌TCS(YhcSR)控制着细菌生长所需的基因/操纵子。我们的假设是基于我们的初步数据，即1)YhcS(组氨酸激酶)表达下调以一种剂量依赖的方式抑制细菌生长；2)YhcS或YhcR的过度表达也阻碍细菌的生长；以及3)YhcR编码一个反应调节因子(DNA结合蛋白)，在各种革兰氏阳性病原体中有许多不同的同源物。因此，本提案的目的是确定yhcSR系统的特征，识别由yhcSR控制的基因/操纵子，并确定yhcSR直接调控的细菌生存所需的基因/操纵子。我们将追求以下具体目标来检验我们的中心假设。 首先，我们将表征yhcSR系统，以说明为什么它对细菌生长很重要。其次，我们将确定yhcSR直接调控的靶基因，并确定所鉴定的基因产物对细菌生长的重要性。第三，我们将确定是什么控制了yhcSR的表达。这些结果不仅将为细菌生理学的调节机制提供新的见解，而且还可能导致确定新的靶点，以开发预防和治疗干预措施。

DESCRIPTION (provided by applicant): Staphylococcus aureus is a major community and hospital-acquired pathogen causing superficial skin and life-threatening infections worldwide. The continued emergence of multiple-antibiotic resistant strains of S. aureus, especially methicillin and vancomycin-intermediate resistant strains, is of significant public health concern. This organism has evolved into a series of two-component signal transduction systems (TCS) in order to sense its immediate surroundings and to modulate cellular responses and the expression of virulence genes. Our long-term goals are to elucidate the regulatory mechanisms controlling the expression of genes involved in critical pathways in order to identify novel targets for delivering efficacious preventive and/or therapeutic agents against S. aureus. The specific hypothesis is that a novel S. aureus TCS (yhcSR} controls the genes/operons required for bacterial growth. Our hypothesis has been formulated on the basis of our preliminary data that 1) the down-regulation of YhcS (histdine kinase) expression inhibits bacterial growth in a dose-dependent manner; 2) the over-expression of either YhcS or YhcR also impedes bacterial growth; and 3) yhcR encodes a response regulator (DNA-Binding protein) and has many different homologs in various Gram-positive pathogens. Therefore, the objectives of this proposal are to characterize the yhcSR system, identify genes/operons that are controlled by yhcSR, and determine the genes/operons that yhcSR directly regulates, which are required for bacterial survival. We will pursue the following specific aims to test our central hypothesis. First, we will characterize the yhcSR system to address why it is important for bacterial growth. Second, we will identify the target genes directly regulated by yhcSR and determine the importance of the identified gene products for bacterial growth. Third, we will determine what controls yhcSR expression. These results will not only provide new insights into the regulatory mechanisms of bacterial physiology, but may also lead to the identification of novel targets for developing preventive and therapeutic interventions.