Synthetic Ligands for Modulating Bacterial Communication

用于调节细菌通讯的合成配体

• 批准号: 7742173
• 负责人: Helen E. Blackwell
• 金额: $ 23.27万
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7742173
• 关键词: Address; Affect; Affinity; Agonist; Attenuated; Bacteria; Binding; Binding Sites; Biochemical; Biological; Biological Assay; Cell Communication; Cells; Chemicals; Chronic; Combinatorial Chemistry Techniques; Communicable Diseases; Communication; Communities; Development; Evaluation; Generations; Goals; Gram-Negative Bacteria; Health; Human; Infection; Intercept; Kinetics; Language; Laser Scanning Confocal Microscopy; Libraries; Ligand Binding; Ligands; Mass Spectrum Analysis; Methods; Microbial Biofilms; Molecular; Molecular Conformation; Pathway interactions; Population Density; Property; Public Health; Receptor Activation; Reporter Genes; Repression; Research; Research Personnel; Route; S Phase; Signal Pathway; Signal Transduction; Solid; Structure; Surface Plasmon Resonance; Techniques; Testing; Virulence; Work; analog; antimicrobial; base; biophysical chemistry; combinatorial; design; flexibility; improved; inhibitor/antagonist; method development; novel therapeutic intervention; pathogenic bacteria; programs; promoter; quorum sensing; receptor; receptor binding; receptor expression; research study; scaffold; small molecule

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.

这个项目的主要目标是设计、合成和评估新的化学诱导剂 调节细菌中的细胞间通讯机制。细菌与人交流的能力 它们自身和作为一个群体的功能在传染病的发展中至关重要。革兰氏阴性 细菌使用小分子(或自身诱导物)及其同源蛋白受体的化学“语言” 以一种被称为“群体感应”的现象来感知它们当地的种群密度。在人口众多的地方 密度，致病细菌利用这种感知机制组织成结构化的群落，称为 生物膜和激活毒力途径是无数慢性感染的基础。最新进展 控制细菌群体感应和减少生物被膜形成的方法将产生重大影响 对人类健康的影响。我们假设合成的配体可以用来截取细菌的自身诱导剂。 受体结合并调节群体感应和生物膜的形成。这一战略将使我们能够 解决细菌传播领域的基本问题。首先，我们发现的配体将 揭示对小分子的促进或抑制至关重要的分子水平特征 法定人数感应。其次，合成配体可以用来探测分子的构象要求 自身诱导物受体的激活和失活。第三，量身定制的更高亲和力的配体将使隔离成为可能 在众多顽固不化的自身诱导剂受体中。我们已经开发了一种方法来解决这些问题 将合成有机、组合和生物物理化学技术相结合的问题，以快速 识别调节细菌群体感应的新分子。这项拟议的研究有三项 具体目标：(1)设计和合成针对细菌自身诱导受体的新配体，(2) 测试合成配体对相关病原菌群体感应的影响，以及(3) 用现代技术表征非天然配体与自身诱导物受体的结合作用 生物物理技术。我们已经通过合成在我们的初步研究中验证了这种方法 以及一组新的群体感应小分子拮抗剂的鉴定。 相关性：细菌使用化学信号引发大多数人类感染。发现了 阻断这些信号通路的方法将对公众健康产生深远影响。有一个 全球迫切需要新的抗菌疗法；通过以下方式干扰细菌毒力的能力 拦截细菌通讯网络代表了一种全新的治疗方法， 临床上很及时。

项目成果

Evaluation of a focused library of N-aryl L-homoserine lactones reveals a new set of potent quorum sensing modulators.

• DOI: 10.1016/j.bmcl.2008.07.089
• 发表时间: 2008-11-15
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• 影响因子: 2.7
• 作者: Geske, Grant D.;Mattmann, Margrith E.;Blackwell, Helen E.
• 通讯作者: Blackwell, Helen E.

Attenuation of quorum sensing in the pathogen Acinetobacter baumannii using non-native N-Acyl homoserine lactones.

• DOI: 10.1021/cb300351x
• 发表时间: 2012-10-19
• 期刊: ACS CHEMICAL BIOLOGY
• 影响因子: 4
• 作者: Stacy, Danielle M.;Welsh, Michael A.;Rather, Philip N.;Blackwell, Helen E.
• 通讯作者: Blackwell, Helen E.

Potent and selective synthetic modulators of a quorum sensing repressor in Pseudomonas aeruginosa identified from second-generation libraries of N-acylated L-homoserine lactones.

• DOI: 10.1002/cbic.201000708
• 发表时间: 2011-04-11
• 期刊: CHEMBIOCHEM
• 影响因子: 3.2
• 作者: Mattmann, Margrith E.;Shipway, Patrick M.;Heth, Nicole J.;Blackwell, Helen E.
• 通讯作者: Blackwell, Helen E.

Small molecule macroarray construction via palladium-mediated carbon-carbon bond-forming reactions: highly efficient synthesis and screening of stilbene arrays.

• DOI: 10.1002/chem.200903445
• 发表时间: 2010-03-01
• 期刊: CHEMISTRY-A EUROPEAN JOURNAL
• 影响因子: 4.3
• 作者: Frei, Reto;Blackwell, Helen E.
• 通讯作者: Blackwell, Helen E.

Solid-phase and microwave-assisted syntheses of 2,5-diketopiperazines: small molecules with great potential.

2,5-二酮哌嗪的固相和微波辅助合成：具有巨大潜力的小分子。

• DOI: 10.2174/138620707783220365
• 发表时间: 2007
• 期刊: Combinatorial chemistry & high throughput screening
• 影响因子: 1.8
• 作者: O'Neill,JenniferC;Blackwell,HelenE
• 通讯作者: Blackwell,HelenE