Inhibition of Interspecies Bacterial Quorum Sensing

种间细菌群体感应的抑制

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7488851
• 关键词: Antibiotic Therapy; Bacillus anthracis; Back; Bacteria; Biological Assay; Borates; Chemistry; Collaborations; DPYD gene; Development; Dihydropyrimidine Dehydrogenase; Drug Kinetics; Effectiveness; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Evaluation; Goals; In Vitro; Institutes; Libraries; Pathogenicity; Property; Range; Resistance development; Roentgen Rays; Salmonella typhimurium; Signal Transduction; Source; Structural Protein; Structure; System; Testing; Vibrio; Vibrio cholerae; Work; analog; bacterial genetics; base; design; feeding; high throughput screening; in vivo; inhibitor/antagonist; killings; novel; novel strategies; pathogen; pathogenic bacteria; quorum sensing; small molecule; structural biology

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。LuxS负责在许多不同种类的致病菌中产生关键的群体感应分子AI-2。长期目标是更全面地了解物种间群体感应功能，这意味着一种控制一些最严重的细菌病原体（如霍乱弧菌和炭疽芽孢杆菌）致病性的新方法。LuxS产生DPD，这是自发相互转化分子和硼酸酯的来源，统称为AI-2。设计、合成和评估底物模拟物、过渡态模拟物和基于机制的LuxS抑制剂是这个项目的主要目标。这些设计将基于蛋白质结构信息和LuxS的作用机制。所设计的抑制剂将在体外优化活性，然后在体内优化其有效性和良好的药代动力学。有效的抑制剂将与天然LuxS结晶，以提供活性酶/抑制剂相互作用的详细结构。化合物文库的高通量筛选将与Broad研究所合作进行，使用一种完善的测定LuxS体内和体外活性的方法。目标是确定可以作为LuxS抑制剂的新结构类型。x射线晶体学研究将提供新抑制剂与LuxS相互作用的信息，这些信息将反馈到抑制剂的设计中。在高度敏感的哈维弧菌生物荧光试验中进行初步评估后，有希望的抑制剂将在两种临床重要病原体，鼠伤寒沙门氏菌和霍乱弧菌中进行测试。这些研究可能会导致新的广谱细菌控制剂的开发。根据一种不杀死细菌的新原理，这种方法不太可能像大多数传统抗菌药那样迅速产生耐药性。该项目旨在发现新的小分子，通过抑制AI-2信号系统来抑制细菌群体感应。AI-2系统似乎在广泛的细菌中控制致病性，有效的抑制剂将作为探针，在不同物种和多物种菌落中研究该系统。具有适当药理学特性的有效抑制剂将成为控制病原菌的全新方法的候选者，作为传统抗生素治疗的补充或替代。