Chemical Strategies to Manipulate A1-2 Signaling in Bacterial Pathogens

操纵细菌病原体中 A1-2 信号传导的化学策略

• 批准号: 8264553
• 负责人: Kim Janda
• 金额: $ 47万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8264553
• 关键词: Agonist; Alkynes; Amino Acid Sequence; Anabolism; Anthrax disease; Anti-Bacterial Agents; Antibiotic Resistance; Azides; Bacillus anthracis; Bacteria; Bacterial Infections; Behavior; Binding; Binding Proteins; Biochemical; Biological; Bioluminescence; Biotin; Cells; Chemicals; Chronic; Clostridium difficile; Coin; Communities; Complex; Copper; Cues; Dental caries; Disease; Enzymes; Evaluation; Family member; Future; Gene Expression; Genes; Helicobacter pylori; Human; Individual; Investigation; Light; Maps; Mass Spectrum Analysis; Mediating; Methodology; Microbial Biofilms; Molecular; Nature; Oligopeptides; Organ; Peptide Sequence Determination; Phase; Phenotype; Photoaffinity Labels; Physiological; Population; Population Density; Positioning Attribute; Preparation; Process; Production; Protein Analysis; Proteins; Proteomics; Reaction; Regulation; Reporting; Research Institute; Route; Salmonella typhimurium; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Solid; Staphylococcus epidermidis; Streptococcus mutans; Structure; System; Therapeutic; Tissues; Virulence; Virulence Factors; Wound Infection; analog; base; clinically relevant; cycloaddition; design; genetic regulatory protein; homoserine lactone; insight; microbial; pathogen; pathogenic bacteria; prevent; professor; protein complex; protein expression; protein profiling; public health relevance; quorum sensing; receptor; research study; response; scaffold; therapeutic development

DESCRIPTION (provided by applicant): Quorum sensing (QS) has evolved as a means for bacterial communities to regulate gene expression in response to environmental cues in a coordinated manner. Each cell of the population produces and secretes signaling molecules, called autoinducers, and responds to these molecules, which thus serve as indicators of the population density. QS circuits control complex bacterial behaviors, such as bioluminescence, virulence, antibiotic resistance, and biofilm formation. QS systems have been discovered in Gram-negative and -positive bacteria and a variety of molecules, e.g. oligopeptides and acyl homoserine lactones, have been identified as autoinducers. A distinct third class of QS molecules are autoinducers derived from the precursor (S)-4,5-dihydroxy-2,3-pentanedione (DPD). So far, two distinct members of this family have been structurally identified. The luxS gene encoding the enzyme responsible for the final step in the biosynthesis of DPD, has been identified in over 55 bacterial species, both Gram-positive and -negative bacteria, including many clinically relevant pathogens. We have designed a series of chemical, biochemical, and biological experiments to examine and evaluate the molecular mechanisms that define AI-2 recognition by bacterial cells. In addition these investigations will help elucidate the bioactivity of DPD in bacterial systems, as well as to obtain molecules that possess agonistic or antagonistic signaling activity. The specific aims of our proposal are: 1) Synthesis of DPD/AI-2 Agonists and Antagonists; 2) Mechanistic Investigations of DPD-mediated Effects in Pathogenic Bacteria; 3) Elucidation of the Cellular Recognition of AI-2; and 4) Proteomic analysis of AI-2 Quorum Sensing-regulated Processes. In total, we believe that the use of synthetic DPD and systematically designed analogs of DPD/AI-2 in the experimental methodologies outlined in this proposal will provide new biochemical and microbiological insights into DPD-/AI-2-based QS systems and will help to evaluate the therapeutic value of AI-2-dependent QS as new leads for the antibacterial strategies. PUBLIC HEALTH RELEVANCE: Microbial cell-to-cell signaling has been coined "quorum sensing". It controls many bacterial processes, such as antibiotic resistance and biofilm formation, which represents a majority of disease states where chronic bacterial infection leads to tissue destruction and loss of organ function. This includes diseases as diverse as dental caries, wound infections, and even anthrax. This proposal is designed to gain insight into the molecular details of quorum sensing and to develop countermeasures to prevent quorum sensing signaling in a wide number of bacteria.

描述（由申请人提供）：法定感应（QS）已进化为细菌群落以协调方式对环境线索响应基因表达的一种手段。人群的每个细胞都会产生并分泌的信号分子，称为自动诱导剂，并对这些分子做出反应，从而充当人口密度的指标。 QS电路控制复杂的细菌行为，例如生物发光，毒力，抗生素耐药性和生物膜形成。 QS系统已在革兰氏阴性和阳性细菌以及各种分子中发现，例如寡肽和酰基同素内酯已被鉴定为自动诱导剂。不同的第三类QS分子是源自前体的自动诱导剂-4,4,5-二羟基-2,3-戊二酮（DPD）。到目前为止，该家族的两个不同成员在结构上已经确定。编码负责DPD生物合成的酶的LUXS基因已在55种超过55种细菌物种中鉴定出革兰氏阳性和阴性细菌，包括许多临床相关的病原体。我们设计了一系列化学，生化和生物学实验，以检查和评估定义细菌细胞识别AI-2识别的分子机制。此外，这些研究将有助于阐明细菌系统中DPD的生物活性，并获得具有激动或拮抗信号活性的分子。我们提案的具体目的是：1）DPD/AI-2激动剂和拮抗剂的合成； 2）DPD介导的致病细菌作用的机械研究； 3）阐明AI-2的细胞识别； 4）AI-2法群传感调节过程的蛋白质组学分析。 总的来说，我们认为在本提案中概述的实验方法中，使用合成DPD和系统设计的DPD/AI-2的类似物将提供新的生化和微生物学见解，以对DPD-/ai-2的QS系统有助于评估AI-2依赖性QS的治疗价值作为抗菌策略的新铅。 公共卫生相关性：微生物细胞到细胞信号传导已被创造为“法定感应”。它控制着许多细菌过程，例如抗生素耐药性和生物膜形成，这代表了大多数疾病状态，在这些疾病状态下，慢性细菌感染导致组织破坏和器官功能的丧失。这包括龋齿，伤口感染甚至炭疽等疾病。该提案旨在深入了解法定感测的分子细节，并开发对策，以防止各种细菌中的法规传感信号传导。