Manipulating quorum sensing system to control pathogenicity in Vibrio cholerae

操纵群体感应系统控制霍乱弧菌的致病性

• 批准号: 8649279
• 负责人: Alice Kyungsun Min
• 金额: $ 4.72万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2019-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649279
• 关键词: Acute; Agonist; Amino Acids; Bacteria; Behavior; Binding; Biochemical; Biological Assay; Cell Communication; Cell Signaling Process; Cell physiology; Cells; Cholera; Communities; Detection; Development; Diarrhea; Digestive System Disorders; Disease; Genetic; Goals; Human; In Vitro; Infection; Ligands; Maps; Membrane; Microbial Biofilms; Molecular; Mutagenesis; N-(3-oxohexanoyl)-3-aminodihydro-2(3H)-furanone; Pathogenicity; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Population Density; Production; Public Health; Series; Signal Transduction; Signaling Molecule; Source; Specificity; Stomach; Structure; Synthesis Chemistry; System; Therapeutic; Vibrio; Vibrio cholerae; Virulence; Virulence Factors; extracellular; genetic analysis; in vivo; insight; interest; novel therapeutics; pathogen; pathogenic bacteria; public health relevance; quorum sensing; receptor; research study; response; sensor; sensor histidine kinase

DESCRIPTION (provided by applicant): The overarching goal of this study is to understand the molecular mechanisms underpinning bacterial collective behaviors required for causing acute gastric infections in humans. To explore this, quorum sensing, the process of cell-cell communication in the pathogenic bacterium Vibrio cholerae will be studied. V. cholerae is the etiological agent of the disease cholera, a severe diarrheal condition that is a source of enormous public health concern in the developing world. Quorum sensing in V. cholerae depends on the production, release, detection, and response to extracellular signaling molecules called autoinducers. Group-wide detection of autoinducers allows V. cholerae to synchronously alter its behavior in response to changes in the population density and species composition of the vicinal bacterial community. In V. cholerae, quorum sensing is activated by two autoinducers, CAI-1 and AI-2. CAI-1, the dominant signal, is detected by the membrane-bound histidine sensor kinase, CqsS, and these are the focus of this study. In V. cholerae, quorum sensing represses biofilm formation and virulence factor production. Thus, molecules that activate quorum sensing ("pro-quorum sensing" molecules) have the potential to repress virulence in V. cholerae and to be developed into therapeutics. The goal of this study is to define the molecular mechanism by which specific molecules are recognized by the CqsS receptor and determine how they elicit the quorum sensing response. Particularly interesting are ligand- receptor interactions between CqsS and the recently discovered CqsS agonist called WYZ301. WYZ301 is structurally distinct from CAI-1 and yet it potently agonizes quorum sensing. Studying new molecules, such as WYZ301, should greatly enhance the understanding of how CqsS interacts with ligands to generate the quorum sensing response. More generally, these studies will contribute to the development of novel therapeutics for V. cholerae, closely related pathogenic vibrios, as well as other diarrhea-causing bacteria that use quorum sensing for collective behaviors, including virulence.

描述(由申请人提供)：这项研究的首要目标是了解导致人类急性胃部感染所需的细菌集体行为的分子机制。为了探索这一点，群体感应，将研究霍乱弧菌的细胞间通讯过程。霍乱弧菌是霍乱的病原体，霍乱是一种严重的腹泻疾病，在发展中国家是一个巨大的公共卫生问题的来源。霍乱弧菌群体感应依赖于细胞外信号分子自身诱导物的产生、释放、检测和反应。对自体诱导子的全群检测使霍乱弧菌能够同步改变其行为，以应对邻近细菌群落的种群密度和物种组成的变化。在霍乱弧菌中，群体感应被两个自动诱导剂激活，即AI-1和AI-2。主要信号CaI-1是通过膜结合的组氨酸传感器激酶CqsS检测到的，这些都是本研究的重点。在霍乱弧菌中，群体感应抑制生物膜的形成和毒力因子的产生。因此，激活群体感应的分子(“群体感应”分子)有可能抑制霍乱弧菌的毒力，并被开发成治疗药物。这项研究的目标是确定 特定分子被CqsS受体识别并决定它们如何引发群体感应反应的分子机制。特别有趣的是CqsS和最近发现的名为WYZ301的CqsS激动剂之间的配体-受体相互作用。WYZ301在结构上与CAI-1不同，但它强烈地困扰着群体感应。研究新的分子，如WYZ301，应该会大大提高对CqsS如何与配体相互作用产生群体感应反应的理解。更广泛地说，这些研究将有助于开发治疗霍乱弧菌、密切相关的致病弧菌以及其他利用群体感应进行集体行为(包括毒力)的腹泻细菌的新疗法。