Quorum Sensing in Burkolderia mallei: an antivirulence therapeutic

鼻疽伯克氏菌的群体感应：一种抗毒疗法

• 批准号: 8236992
• 负责人: Everett P Greenberg
• 金额: $ 30.59万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236992
• 关键词: Animal Model; Animals; Anti-Infective Agents; Bacteria; Behavior; Belief; Burkholderia mallei; Categories; Cells; Centers of Research Excellence; Development; Discrimination; Elements; Emerging Communicable Diseases; Genes; Genetic; Individual; Infection; Investigation; Laboratories; Lead; Life; Light; Malleus; Methods; Modeling; Motion; Mutation; National Institute of Allergy and Infectious Disease; Nature; Population; Procedures; Pseudomonas; Pseudomonas aeruginosa; Recruitment Activity; Regulation; Regulon; Reporter; Research; Role; Scientist; Signal Transduction; Staging; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Virulence; Virulence Factors; Work; biodefense; efficacy testing; high throughput screening; inhibitor/antagonist; interest; knowledge base; member; pathogen; programs; promoter; quorum sensing; receptor; research study; small molecule; therapeutic development; tool

Bacterial quorum sensing involves small molecule cell-cell siganling that allows coordination of behavior among individual cells in a population. Quorum sensing in the NIAID Category B Priority Pathogen Burkholderia mallei holds a particular interest. First, like for certain other pathogens such as Pseudomonas aeruginosa quorum sensing is involved in virulence of B. mallei. Efforts to develop anti-Pseudomonas quorum sensing inhibitors have been hindered by the lack of adequate animal models for Pseud0monas infections. The availability of such models for B. mallei affords us the ability to put a program in motion that will eventually lead to tests of efficacy for small molecule inhibitors in animal models. Second, a common belief among scientists working on quorum sensing is that it allows a pathogen (or at least a symbiont) to discriminate between a host and a free-living state, Burkholderia mallei is an obligate animal pathogen with no known environmental reservoir. Quorum sensing must be involved in discrimination of different stages or types of infections by this pathogen. Finally, a most obviously, quorum sensing in B. Mallei is a target for anti-S. mallei therapeutic development. Dr. Greenberg proposes to adapt his recently developed quorum sensing reporter system for use in a high-throughput screen for inhibitors. Further experiments will be aimed at identification of quorum-controlled fi. mallei genes. These experiments will involve promoter-trap technology and require the construction of a quorum-sensing regular "gutted strain of B. mallei and or the closely related fi. thailandensis. A new counter-selection method for insertional gene inactiviation in B. thailandensis will be described, as will plans to extend the procedure to B. meillei. This method for generating mutations in members of the B. mallei group represents a major advance that will overcome a current obstacle faced by fi. mallei biologists.

细菌群体感应涉及小分子细胞-细胞信号传导，允许行为协调 在群体中的单个细胞中。NIAID B类优先病原体中的群体感应 鼻疽伯克霍尔德氏菌引起了特别的兴趣。首先，像某些其他病原体，如假单胞菌 铜绿假单胞菌群体感应参与了B的毒力。鼻疽开发抗假单胞菌的努力 由于缺乏足够的假单胞菌动物模型，群体感应抑制剂的研究受到阻碍 感染.这些模型对B的可用性。malei使我们有能力启动一个程序， 将最终导致在动物模型中测试小分子抑制剂的功效。第二，共同 研究群体感应的科学家们相信，它允许病原体（或至少是共生体） 为了区分宿主和自由生活状态，鼻疽伯克霍尔德氏菌是一种专性动物病原体， 没有已知的环境水库。群体感应必须参与不同阶段的区分， 这种病原体的感染类型。最后，一个最明显的，在B中的群体感应。马里是一个目标， 抗S.鼻疽治疗进展格林伯格博士建议调整他最近开发的法定人数 用于高通量筛选抑制剂的传感报告系统。进一步的实验将针对 在确定法定人数控制的FI。鼻疽基因这些实验将涉及启动子陷阱 技术，并需要构建一个群体感应定期“掏空菌株的B。鼻疽和或鼻疽 关系密切的FI。泰国茶一种新的B中插入基因失活的反选择方法 将描述thailandensis，以及将该过程扩展到B的计划。梅莱这种生成方法 B成员的突变。马累群代表了一个重大的进步， 遇到的障碍，FI。鼻疽生物学家