Inhibition of Interspecies Bacterial Quorum Sensing

种间细菌群体感应的抑制

基本信息

批准号：
7488851
负责人：
MARTIN F SEMMELHACK
金额：
$ 23.25万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2009-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): This project is an integrated effort of chemistry, structural biology, and bacterial genetics with a focus on the enzyme LuxS. LuxS is responsible for producing the key quorum sensing molecules, AI-2, in many different species of pathogenic bacteria. A long range goal is a more complete understanding of the inter- species quorum sensing function with the implication of a new approach to control the pathogenicity of some of the most serious bacterial pathogens, such as Vibrio cholerae and Bacillus anthracis. LuxS produces DPD, the source of spontaneously interconverting molecules and borate diesters that are collectively called AI-2. Design, synthesis, and evaluation of substrate analog, transition state analog, and mechanism-based inhibitors of LuxS is a major goal of this project. The designs will be based on protein structural information and the proposed mechanism of action of LuxS. The designed inhibitors will be optimized for activity in vitro, and then refined for effectiveness and favorable pharmacokinetics in vivo. Effective inhibitors will be crystallized with native LuxS to provide a detailed structure of the active enzyme/inhibitor interaction. High throughput screening of compound libraries will be undertaken in collaboration with the Broad Institute, using a well-established assays for LuxS activity in vivo and in vitro. The goal is to identify new structural types that can function as inhibitors of LuxS. An X-ray crystallographic effort will provide information on the interaction of new inhibitors with LuxS, and this information will feed back into the inhibitor design. After initial evaluation in the highly sensitive bioluminescent Vibrio harveyi bioassay, promising inhibitors will be tested in the two clinically important pathogens, Salmonella typhimurium and Vibrio cholerae. These studies may result in the development of novel broad-spectrum bacterial control agents. Working by a new principle that does not kill the bacteria, this approach is unlikely to suffer from the rapid development of resistance as observed with most traditional anti-bacterials. This project aims to discover new small molecules that will inhibit quorum sensing in bacteria through the inhibition of the AI-2 signaling system. The AI-2 system appears to control pathogenicity over a broad spectrum of bacteria, and potent inhibitors will serve as probes to investigate this system in different species as well as in multi-species colonies. Potent inhibitors with appropriate pharmacological properties will be candidates for an entirely new approach to control of pathogenic bacteria, as a supplement or replacement for conventional antibiotic therapy.

描述（由申请人提供）：该项目是化学，结构生物学和细菌遗传学的综合努力，重点是酶。 Luxs负责在许多不同种类的致病细菌中生成关键的群体传感分子AI-2。一个远距离目标是对种类群体相互感应功能的更完整理解，这意味着一种新方法来控制某些最严重的细菌病原体的致病性，例如颤音霍乱和炭疽芽孢杆菌。 Luxs生产DPD，这是自发互连分子和硼酸盐的二聚体的来源，这些分子被共同称为AI-2。底物类似物，过渡状态类似物和基于机理的lux的设计，合成和评估是该项目的主要目标。这些设计将基于蛋白质结构信息和提议的Lux作用机理。设计的抑制剂将用于体外活性，然后在体内进行有效性和有利的药代动力学。有效的抑制剂将用天然lux结晶，以提供活性酶/抑制剂相互作用的详细结构。使用良好的luxs活动在体内和体外进行卢克斯活动的测定法，将对化合物图书馆进行高吞吐量筛选。目的是确定可以用作Lux抑制剂的新结构类型。 X射线晶体学工作将提供有关新抑制剂与Luxs相互作用的信息，此信息将反馈到抑制剂设计中。在高度敏感的生物发光颤音Harveyi生物测定中进行了初步评估后，将在两种临床上重要的病原体，沙门氏菌伤寒沙门氏菌和弧菌霍乱中测试有希望的抑制剂。这些研究可能导致新型广谱细菌控制剂的发展。这种方法是通过新原则的工作，这种方法不太可能遭受大多数传统抗菌剂观察到的抗药性的快速发展。该项目旨在发现新的小分子，这些分子将通过抑制AI-2信号系统来抑制细菌中的群体传感。 AI-2系统似乎控制着广泛细菌的致病性，并且有效的抑制剂将作为在不同物种以及多种物种菌落中研究该系统的探针。具有适当药理特性的有效抑制剂将成为控制致病细菌的全新方法，作为常规抗生素疗法的补充或替代方法。