A Novel Essential Regulator of Staphylococcus aureus

描述（由申请人提供）：金黄色葡萄球菌是一种主要的社区和医院获得性病原体，在世界范围内引起浅表皮肤感染和危及生命的感染。持续出现的多重耐药金黄色葡萄球菌菌株，特别是甲氧西林和万古霉素中间耐药菌株，是一个重大的公共卫生问题。这种生物已经进化成一系列双组分信号转导系统（TCS），以感知其周围环境并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中基因表达的调控机制，以确定新的靶点，为金黄色葡萄球菌提供有效的预防和/或治疗药物。具体的假设是一种新的金黄色葡萄球菌TCS （yhcSR）控制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：1)下调YhcS（组氨酸激酶）表达以剂量依赖的方式抑制细菌生长；2) YhcS或YhcR的过表达也会阻碍细菌生长；3) yhcR编码应答调节因子（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，本提案的目标是表征yhcSR系统，鉴定受yhcSR控制的基因/操纵子，确定yhcSR直接调控的基因/操纵子，这些基因/操纵子是细菌生存所必需的。我们将追求以下具体目标来检验我们的中心假设。

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.