Bacterial Quorum Sensing as Target for Anti-Infective Immunotherapy

细菌群体感应作为抗感染免疫治疗的目标

基本信息

批准号：
8015378
负责人：
Gunnar Joerg Floris Kaufmann
金额：
$ 46.53万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-12 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8015378
关键词：
AIDS/HIV problem Affinity American Animal Model Anti-Infective Agents Antibiotic Resistance Antibodies Area Bacteria Bacterial Antibiotic Resistance Bacterial Infections Behavior Control Bioluminescence Carrier Proteins Cell Communication Cells Centers for Disease Control and Prevention (U.S.)Chemicals Chemistry Coin Communication Complex Data Development Engineering Gene Expression Generations Gram-Negative Bacteria Gram-Positive Bacteria Haptens Health Human Immune response Immune system Immunoglobulin A Immunoglobulins Immunotherapeutic agent Immunotherapy In Vitro Infection Investigation Length Mammalian Cell Microbial Biofilms Molecular Biology Oligopeptides Passive Immunization Pathogenesis Phage Display Population Process Production Property Pseudomonas aeruginosa Reagent Research Research Proposals Signal Transduction Signaling Molecule Solid Staphylococcus aureus System Technology Testing Therapeutic Therapeutic Agents Vaccination Vaccines Variant Vibrio fischeri Virulence Virulence Factors antimicrobial drug base clinically relevant combat cytotoxicity design disorder prevention fighting homoserine lactone improved in vitro Assay in vivo member methicillin resistant Staphylococcus aureus microbial mouse model novel novel strategies pathogen prevent programs prophylactic protein metabolite quorum sensing research study small molecule therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The initial discovery that Gram-negative bacteria, such as Vibrio fischeri and Pseudomonas aeruginosa, employ small diffusible molecules, namely N-acyl homoserine lactones, to globally regulate the production of secondary metabolites and proteins, initiated a new area in microbiological research, the field of quorum sensing. Subsequently, other quorum sensing systems and signaling molecules have been identified, including oligopeptides in Gram-positive bacteria, such as Staphylococcus aureus. Quorum sensing systems seem to be evolutionary conserved and many of them are involved in the control of bacterial pathogenesis. With the emergence of more highly antibiotic-resistant bacterial strains ("superbugs"), most notably methicillin-resistant S. aureus (MRSA) and P. aeruginosa, new approaches for combating bacterial infections are desperately needed. In fact, the Center for Disease Control and Prevention (CDC) has estimated that 94,000 invasive MRSA infections occurred in the U.S in 2005 and more than 19,000 Americans died from these infections - more than annual HIV/AIDS casualties. Bacterial quorum sensing signaling molecules might represent such new targets for anti-infective immunotherapy. The powerful combination of chemistry and molecular biology will be harnessed to provide a solid rational basis for quorum quenching therapeutic agents. The specific aims of our R01 application are: (1) Therapeutic targeting of AHL-based Quorum Sensing in Pseudomonas aeruginosa; and (2) The agr Quorum Sensing System in Staphylococcus aureus as target for Immunotherapy. PUBLIC HEALTH RELEVANCE: Bacterial pathogens, even so-called antibiotic-resistant "super bugs", utilize cell-to-cell signaling, a process termed "quorum sensing", to control their virulence. The molecules that bacteria use for their communication represent attractive targets for anti-infective therapy as the scavenging of the small compounds would render the bacteria harmless. We propose to develop antibodies and harness the immune system in general for the disruption of bacterial quorum sensing and thus, a new strategy in fighting bacterial infections.

描述（由申请人提供）：最初发现革兰氏阴性细菌，例如费氏弧菌和铜绿假单胞菌，利用小可扩散分子，即N-酰基高丝氨酸内酯，来全局调节次级代谢产物和蛋白质的产生，开创了一种新的方法微生物研究领域，群体感应领域。随后，其他群体感应系统和信号分子也被鉴定出来，包括金黄色葡萄球菌等革兰氏阳性细菌中的寡肽。群体感应系统似乎是进化保守的，其中许多参与细菌发病机制的控制。随着更多耐抗生素细菌菌株（“超级细菌”）的出现，尤其是耐甲氧西林金黄色葡萄球菌（MRSA）和铜绿假单胞菌，迫切需要对抗细菌感染的新方法。事实上，美国疾病控制与预防中心 (CDC) 估计 2005 年美国发生了 94,000 例侵入性 MRSA 感染，超过 19,000 名美国人死于这些感染，超过每年艾滋病毒/艾滋病的死亡人数。细菌群体感应信号分子可能代表抗感染免疫治疗的新靶点。化学和分子生物学的强大结合将被用来为群体猝灭治疗剂提供坚实的合理基础。我们的 R01 应用的具体目标是：（1）基于 AHL 群体感应的铜绿假单胞菌的治疗靶向； (2) 以金黄色葡萄球菌中的 agr 群体感应系统作为免疫治疗的靶标。公共健康相关性：细菌病原体，甚至所谓的抗生素耐药性“超级细菌”，都利用细胞间信号传导（一种称为“群体感应”的过程）来控制其毒力。细菌用于通讯的分子代表了抗感染治疗的有吸引力的目标，因为清除这些小化合物将使细菌变得无害。我们建议开发抗体并利用免疫系统来破坏细菌群体感应，从而形成对抗细菌感染的新策略。