Synthetic Ligands for Modulating Bacterial Communication

用于调节细菌通讯的合成配体

基本信息

批准号：
7037720
负责人：
Helen E. Blackwell
金额：
$ 20.21万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2010-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The broad goal of this project is the design, synthesis, and evaluation of new chemical inducers that modulate cell-cell communication mechanisms in bacteria. The ability of bacteria to communicate with themselves and function as a group is crucial in the development of infectious disease. Gram-negative bacteria use a chemical 'language' of small molecules (or autoinducers) and their cognate protein receptors to sense their local population densities in a phenomenon known as 'quorum sensing'. At high population densities, pathogenic bacteria use this sensing mechanism to organize into structured communities called biofilms and activate virulence pathways that are the basis for myriad chronic infections. The development of methods to control bacterial quorum sensing and attenuate biofilm formation would have a major impact on human health. We hypothesize that synthetic ligands can be used to intercept bacterial autoinducer/ receptor binding and modulate quorum sensing and biofilm formation. This strategy would allow us to address fundamental questions in the field of bacterial communication. First, the ligands we uncover will reveal the molecular level features that are essential for small molecule promotion or suppression of quorum sensing. Second, synthetic ligands could be used to probe the conformational requirements for autoinducer receptor activation and inactivation. Third, tailored higher affinity ligands would enable isolation of the numerous recalcitrant autoinducer receptors. We have developed an approach to address these questions that integrates synthetic organic, combinatorial, and biophysical chemistry techniques to rapidly identify new molecules that modulate quorum sensing in bacteria. The proposed research has three Specific Aims: (1) To design and synthesize new ligands that target bacterial autoinducer receptors, (2) To test the effects of the synthetic ligands on quorum sensing in relevant pathogenic bacteria, and (3) To characterize the binding interactions of non-native ligands with autoinducer receptors using modern biophysical techniques. We have validated this approach in our preliminary studies through the synthesis and identification of a set of new small molecule antagonists of quorum sensing. Relevance: Bacteria use chemical signals to initiate the majority of human infections. The discovery of methods to block these signaling pathways would have a profound impact on public health. There is an urgent, global need for new antimicrobial therapies; the ability to interfere with bacterial virulence by intercepting bacterial communication networks represents a completely new therapeutic approach and is clinically timely.

描述（由申请人提供）：该项目的广泛目标是对调节细菌细胞通信机制的新化学诱导剂的设计，合成和评估。细菌与自己交流并作为一组发挥作用的能力对于传染病的发展至关重要。革兰氏阴性细菌使用小分子（或自动诱导剂）及其同源蛋白受体的化学“语言”，以一种称为“ Quorum Sensing”的现象来感知其当地人口密度。在较高的人口密度下，致病细菌使用这种感应机制将其组织到称为生物膜的结构化群落中，并激活毒力途径，这是无数慢性感染的基础。控制细菌群体传感和减弱生物膜形成的方法的发展将对人类健康产生重大影响。我们假设合成配体可用于拦截细菌自动诱导剂/受体结合，并调节法规传感和生物膜形成。这种策略将使我们能够解决细菌交流领域的基本问题。首先，我们发现的配体将揭示分子水平的特征，这些特征对于小分子促进或抑制Quorum传感至关重要。其次，合成配体可用于探测自动诱导者受体激活和失活的构象要求。第三，量身定制的较高亲和力配体将使众多顽固的自动诱导剂受体分离。我们已经开发了一种方法来解决这些问题，该问题整合了合成有机，组合和生物物理化学技术，以迅速识别调节细菌中群体传感的新分子。拟议的研究具有三个具体的目的：（1）设计和合成针对细菌自动诱导者受体的新配体，（2）测试合成配体对相关致病细菌中群体传感的影响，以及（3）以使用自动化学技术与现代化技术的结合相互作用来表征与现代化技术的结合相互作用。通过合成和鉴定一组新的小分子拮抗剂的群体感应器，我们在初步研究中验证了这种方法。相关性：细菌使用化学信号启动大多数人类感染。发现阻止这些信号途径的方法将对公共卫生产生深远的影响。对新的抗菌疗法有迫切的全球需求；通过拦截细菌通信网络来干扰细菌毒力的能力代表了一种全新的治疗方法，并且在临床上是及时的。