Screen for Quorum Sensing Molecular Inhibitors (RMI)

群体感应分子抑制剂 (RMI) 的筛选

• 批准号: 7019299
• 负责人: VANESSA SPERANDIO
• 金额: $ 7.8万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7019299
• 关键词: Escherichia coli 0157:H7; HeLa cells; SDS polyacrylamide gel electrophoresis; antibacterial agents; bacteria infection mechanism; bacterial genetics; biological signal transduction; cell cell interaction; chemical registry /resource; drug resistance; gene expression; gene induction /repression; high throughput technology; inhibitor /antagonist; quorum sensing; transcription factor; virulence

DESCRIPTION (provided by applicant): Quorum sensing is a bacterial cell-to-cell signaling system in which communication occurs through hormone like organic compounds referred to as auto-inducers. These auto-inducers then interact with bacterial transcription factors to drive gene expression in a coordinate manner. Quorum sensing has also recently been recognized as a cell-to-cell signaling system amongst prokarytes and eukaryotes. In particular, the AI-3 bacterial signaling system cross-signals with the human epinephrine/norepinephrine signaling system. The AI-3/epinephrine/norepinephrine signaling cascade is present in several bacterial pathogens such as enterohemorrhagic E. coli (EHEC) O157:H7, Salmonella, Shigella, Yersinia, Francisella tularensis, among others. We have extensivelly demonstrated that this signaling system is responsible for activating EHEC virulence genes. Given the widespread nature of this signaling system amongst several bacterial pathogens, and its defined role in EHEC pathogenesis, this proposal aims to identify molecular chemical inhibitors of this quorum sensing system using a high throughput screen (HTS). This screen will use the UT Southwestern chemical compound library to identify inhibitors of AI-3 signaling. We already have preliminary data on primary screens that were performed and Specific Aim 1 of this proposal is designed to validate and confirm these AI-3 inhibitors. Specific Aim 2 will expand the utilization of these inhibitors in several virulence models of EHEC virulence. Given the multi-drug resistance of several bacterial pathogens to conventional antibiotics, and the need to develop novel classes of antimicrobials, these studies may help to generate a whole new class of antimicrobials that can block AI-3 and epinephrine signaling to bacterial pathogens.

描述（由申请人提供）：群体感应是一种细菌细胞间信号传导系统，其中通过称为自诱导剂的激素类有机化合物进行通信。然后，这些自诱导剂与细菌转录因子相互作用，以协调的方式驱动基因表达。群体感应最近也被认为是原核生物和真核生物之间的细胞间信号传导系统。特别是，AI-3 细菌信号系统与人肾上腺素/去甲肾上腺素信号系统交叉发出信号。 AI-3/肾上腺素/去甲肾上腺素信号级联存在于多种细菌病原体中，例如肠出血性大肠杆菌 (EHEC) O157:H7、沙门氏菌、志贺氏菌、耶尔森氏菌、土拉弗朗西斯氏菌等。我们已经广泛证明该信号系统负责激活肠出血性大肠杆菌毒力基因。鉴于该信号系统在多种细菌病原体中的广泛存在，及其在肠出血性大肠杆菌发病机制中的明确作用，本提案旨在使用高通量筛选（HTS）来识别该群体感应系统的分子化学抑制剂。该筛选将使用 UT Southwestern 化合物库来鉴定 AI-3 信号传导的抑制剂。 我们已经获得了初步筛选的初步数据，该提案的具体目标 1 旨在验证和确认这些 AI-3 抑制剂。具体目标 2 将扩大这些抑制剂在几种肠出血性大肠杆菌毒力模型中的应用。鉴于几种细菌病原体对传统抗生素的多重耐药性，以及开发新型抗菌药物的需要，这些研究可能有助于产生一类全新的抗菌药物，可以阻断细菌病原体的 AI-3 和肾上腺素信号传导。