Novel antibacterial target: an essential glycoprotease

新型抗菌靶点：必需的糖蛋白酶

• 批准号: 7097649
• 负责人: Yinduo Ji
• 金额: $ 22.18万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7097649
• 关键词: antibiotics; drug discovery /isolation; emotions; genes; infection; proteins; public health

DESCRIPTION (provided by applicant): The emergence of multi-drug resistant bacterial pathogens, especially methicillin-resistant and vancomycin intermediate-resistant Staphylococcus aureus is generating an enormous public health concern. Many of these pathogens are capable of causing severe and even fatal infections with limited options for therapy. The slowdown in the discovery of novel classes of antibiotics in past several decades and the recent downturn in antibacterial discovery and development in the pharmaceutical industry is making us more vulnerable to emerging resistance. Therefore, there is an urgent need for new, alternative agents for treating multi-drug-resistant pathogens. The recent availability of the complete genome sequences for pathogens enables us to undertake a systematic and comprehensive evaluation of the requirement for each and every gene/operon for both bacterial growth and infection. The gene products essential for bacterial growth in vitro and survival during infection constitute an initial set of validated protein targets that can be optimized and automated screens. Our long-term goal is to identify novel targets for delivering efficacious preventive and/or therapeutic agents against S. aureus infections. The specific hypothesis is that a putative glycoprotease (Gcp) is a novel antibacterial target involved in the pathway required for bacterial survival. However, the biological function of Gcp and its importance for growth and survival remains unclear. Elucidation of the precise function of Gcp will lead to the basis for the development of an in vitro assay, which is indispensable for the drug discovery. Therefore, the objective of this proposal is to determine the biological function of Gcp, identify pathway that Gcp is involved in, and to develop a potential assay. We will pursue the following three specific aims to test our central hypothesis: First, we will characterize the essential putative glycoprotease of S. aureus. Second, we will employ microarray technology to identify staphylococcal genes, transcriptions of which are affected by conditional inactivation of putative glycoprotease function. Third, we will utilize proteomic approaches to identify proteins that are affected by down-regulation of gcp expression and compare this data with microarray data.

描述（由申请人提供）：多重耐药细菌病原体的出现，特别是耐甲氧西林和耐万古霉素的金黄色葡萄球菌正在引起巨大的公共卫生问题。其中许多病原体能够引起严重甚至致命的感染，而治疗选择却有限。过去几十年来新型抗生素的发现速度放缓，以及最近制药行业抗菌药物发现和开发的低迷，使我们更容易受到新出现的耐药性的影响。因此，迫切需要新的替代药物来治疗多重耐药病原体。最近获得的病原体完整基因组序列使我们能够对细菌生长和感染的每个基因/操纵子的需求进行系统和全面的评估。细菌体外生长和感染期间生存所必需的基因产物构成了一组经过验证的初始蛋白质靶标，可以对其进行优化和自动化筛选。我们的长期目标是确定针对金黄色葡萄球菌感染提供有效预防和/或治疗药物的新靶点。具体的假设是，假定的糖蛋白酶（Gcp）是一种新的抗菌靶点，涉及细菌生存所需的途径。然而，Gcp 的生物学功能及其对生长和生存的重要性仍不清楚。阐明 Gcp 的精确功能将为开发体外测定奠定基础，这对于药物发现是必不可少的。因此，本提案的目的是确定 Gcp 的生物学功能，识别 Gcp 参与的途径，并开发潜在的检测方法。我们将追求以下三个具体目标来检验我们的中心假设：首先，我们将表征金黄色葡萄球菌的基本假定糖蛋白酶。其次，我们将采用微阵列技术来鉴定葡萄球菌基因，其转录受到假定糖蛋白酶功能的条件失活的影响。第三，我们将利用蛋白质组学方法来鉴定受 gcp 表达下调影响的蛋白质，并将该数据与微阵列数据进行比较。