Synthetic Ligands for Modulating Bacterial Communication

用于调节细菌通讯的合成配体

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7037720
• 关键词: N acylation; antibacterial agents; bacterial proteins; binding sites; biofilm; biotechnology; biotherapeutic agent; butyrolactone; combinatorial chemistry; confocal scanning microscopy; conformation; drug design /synthesis /production; drug screening /evaluation; ligands; mass spectrometry; microorganism culture; mixed tissue /cell culture; molecular probes; photoactivation; piperazines; protein purification; quorum sensing; receptor binding; receptor expression; reporter genes; small molecule; surface plasmon resonance; transcription factor

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）：该项目的总体目标是设计、合成和评估调节细菌细胞间通讯机制的新型化学诱导剂。细菌自我交流和作为一个群体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（或自诱导剂）及其同源蛋白受体的化学“语言”来感知其局部种群密度，这种现象称为“群体感应”。在高种群密度下，病原菌利用这种传感机制组织成称为生物膜的结构化群落，并激活毒力途径，这是多种慢性感染的基础。控制细菌群体感应和减弱生物膜形成的方法的开发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诱导剂/受体结合并调节群体感应和生物膜形成。这一策略将使我们能够解决细菌通讯领域的基本问题。首先，我们发现的配体将揭示对于小分子促进或抑制群体感应至关重要的分子水平特征。其次，合成配体可用于探测自诱导剂受体激活和失活的构象要求。第三，定制的更高亲和力配体将能够分离大量顽固的自诱导剂受体。我们开发了一种方法来解决这些问题，该方法集成了合成有机、组合和生物物理化学技术，以快速识别调节细菌群体感应的新分子。拟议的研究有三个具体目标：（1）设计和合成针对细菌自诱导剂受体的新配体，（2）测试合成配体对相关病原菌群体感应的影响，以及（3）表征结合使用现代生物物理技术非天然配体与自诱导受体的相互作用。我们在初步研究中通过合成和鉴定一组新的群体感应小分子拮抗剂验证了这种方法。相关性：细菌利用化学信号引发大多数人类感染。阻断这些信号通路的方法的发现将对公众健康产生深远的影响。全球迫切需要新的抗菌疗法；通过拦截细菌通讯网络来干扰细菌毒力的能力代表了一种全新的治疗方法，并且在临床上很及时。