Bacterial acyl homoserine lactones as immune modulators and drug targets

作为免疫调节剂和药物靶点的细菌酰基高丝氨酸内酯

基本信息

批准号：
7772996
负责人：
Gunnar Joerg Floris Kaufmann
金额：
$ 23.74万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7772996
关键词：
Acinetobacter baumannii Aerosols Afghanistan Agonist Anti-Infective Agents Antibiotic Resistance Antibiotics Antibodies Ants Bacteria Bacterial Infections Binding Biochemical Biological Biological Assay Biological Process Biological Warfare Bioterrorism Breathing Burkholderia mallei Burkholderia pseudomallei Categories Cell Communication Cell Death Cells Cellular Stress Chemistry Clinical Communication Consultations Data Development Drug Delivery Systems Evaluation Evaluation Studies Event FDA approved Generations Genetic Goals Gram-Negative Bacteria Hand Haptens Immune Immune response Immune system Immunology Immunotherapy In Vitro Infection Iraq Laboratories Lead Leadership Leukocytes Lipopolysaccharides Lung Malleus Mammalian Cell Measurement Messenger RNA Microbe Mitogen-Activated Protein Kinases Modeling Molecular Molecular Biology Monoclonal Antibodies Morbidity - disease rate Multi-Drug Resistance Mus Myelogenous Myeloid Cells Natural Immunity Nosocomial Infections Passive Immunization Pathogenesis Pathway interactions Pattern Pattern recognition receptor Peptidoglycan Phosphorylation Proteins Records Research Research Personnel Research Proposals Resources Role Route Signal Pathway Signal Transduction Signaling Molecule Soldier Solid System Therapeutic Therapeutic Intervention Time Toll-like receptors Virulence Wound Infection Yersinia pestis antimicrobial drug base cell growth cell type chemokine cytokine cytotoxicity experience fighting genetic analysis homoserine lactone in vitro Assay macrophage microbial mouse model novel pathogen prophylactic public health relevance quorum sensing receptor research study resistance factors response therapeutic evaluation

项目摘要

DESCRIPTION (provided by applicant): The overarching goal of this research proposal is to investigate the role of bacterial quorum sensing factors in microbial pathogenesis and to then evaluate an anti-virulence strategy based on quorum quenching against selected emerging pathogens, such Acinetobacter baumannii, Yersinia pestis, Burkholderia mallei, and Burkholderia pseudomallei. These Gram-negative bacteria (with the exception of A. baumannii) are category A (Y. pestis) and B (B. pseudomallei and B. mallei) select pathogens, designated so as they are highly likely to be used in incidents of bioterrorism or biowarfare. While not potentially as lethal as other category A and B pathogens, they still pose significant morbidity threats and if delivered by aerosol would have high infectivity potentials. Currently, the number of FDA approved therapies against such bacterial infections is limited to two or three antibiotics and all only have post exposure indications. Additionally, the antibiotic-based therapy could easily be rendered ineffective by introduction of known resistance factors. Therefore, it is of high importance and significance to develop alternative anti-infective strategies for protection against these pathogens. On the other hand, A. baumannii is emerging as a common multi-drug resistance pathogen in nosocomial infections as well as an increasing threat of causing wound infections seen in U.S. soldiers on the battlefields in Iraq and Afghanistan. All pathogens selected for these studies have been shown to utilize bacterial cell-to- cell communication, also called "quorum sensing". Recently, we and others have shown that bacterial QS systems represent an attractive target for prophylactic and therapeutic intervention. QS signaling is based on the exchange of small diffusible molecules, such as N-acyl homoserine lactones (AHL), which are in fact used by A. baumannii, B. mallei, B. pseudomallei and Y. pestis. Similar to classical pathogen-associated molecular patterns (PAMPs), such as bacterial lipopolysaccharide (LPS), and peptidoglycan, AHLs are only produced by microbial pathogens, but not by the mammalian host. Recent research has revealed that the AHL-based QS molecules exert potent cytotoxicity against macrophages, suggesting an additional role for AHLs in dismantling host innate immunity. Studies conducted by the applicants have provided further evidence that AHLs directly activate signaling events in mammalian cells, including leucocytes, and that these occur through mechanisms distinct from the classical PAMP recognition receptor (PRR) pathways, such as the canonical Toll-like receptor (TLR) and Nod-like receptor (NLR) pathways. Therefore, besides their role in bacterial communication, AHL autoinducers themselves might represent new attractive targets for anti-infective immunotherapy. In this proposal, a powerful combination of chemistry, molecular biology, immunology, and genetic approaches will be harnessed to provide a solid rational basis for the generation, development, and evaluation of anti-autoinducer prophylactic and therapeutic strategies. PUBLIC HEALTH RELEVANCE: The bacteria selected for our studies are either new emerging pathogens that have become highly antibiotic resistant, and thus, problematic in clinical settings or are potential bioterrorism and bioware agents. They have been shown to utilize bacterial cell-to-cell communication, also called "quorum sensing" to control their virulence. The molecules that these bacteria use for their communication represent an attractive target for anti-infective therapy as the scavenging of the small compounds would render the bacteria harmless. In addition, these molecules also subvert the host immune system, thus, enabling the microbes to establish their infection in the first place. We propose to develop antibodies for the disruption of bacterial quorum sensing and thus, to develop a new strategy in fighting bacterial infections.

描述（由申请人提供）：本研究计划的总体目标是研究细菌群体感应因子在微生物发病机制中的作用，然后评估基于群体淬灭针对选定的新兴病原体（例如鲍曼不动杆菌、耶尔森氏菌）的抗毒力策略鼠疫菌、鼻疽伯克霍尔德菌和假鼻疽伯克霍尔德菌。这些革兰氏阴性细菌（鲍曼不动杆菌除外）是 A 类（鼠疫耶尔森氏菌）和 B 类（类鼻疽伯克氏菌和鼻疽伯克氏菌）精选病原体，之所以指定，是因为它们极有可能被用于生物恐怖主义事件或生物战。虽然不像其他 A 类和 B 类病原体那样致命，但它们仍然构成重大的发病威胁，如果通过气溶胶传播，将具有很高的传染性。目前，FDA 批准的针对此类细菌感染的疗法仅限于两种或三种抗生素，并且全部仅具有暴露后适应症。此外，由于引入已知的耐药因素，基于抗生素的疗法很容易变得无效。因此，开发替代的抗感染策略来防御这些病原体具有非常重要的意义。另一方面，鲍曼不动杆菌正在成为医院感染中常见的多重耐药病原体，并且引起伊拉克和阿富汗战场上的美国士兵伤口感染的威胁越来越大。这些研究中选择的所有病原体均已被证明利用细菌细胞间通讯，也称为“群体感应”。最近，我们和其他人已经证明细菌 QS 系统是预防和治疗干预的一个有吸引力的目标。 QS 信号传导基于小可扩散分子的交换，例如 N-酰基高丝氨酸内酯 (AHL)，实际上鲍曼不动杆菌、鼻疽杆菌、伪鼻疽杆菌和鼠疫杆菌都使用这些分子。与细菌脂多糖 (LPS) 和肽聚糖等经典病原体相关分子模式 (PAMP) 类似，AHL 仅由微生物病原体产生，而不是由哺乳动物宿主产生。最近的研究表明，基于 AHL 的 QS 分子对巨噬细胞具有强大的细胞毒性，这表明 AHL 在破坏宿主先天免疫方面发挥着额外的作用。申请人进行的研究提供了进一步的证据，表明AHL直接激活哺乳动物细胞（包括白细胞）中的信号传导事件，并且这些信号传导事件通过不同于经典PAMP识别受体（PRR）途径的机制发生，例如典型的Toll样受体（TLR））和Nod样受体（NLR）途径。因此，除了在细菌通讯中的作用之外，AHL 自诱导剂本身可能代表抗感染免疫治疗新的有吸引力的靶点。在该提案中，将利用化学、分子生物学、免疫学和遗传学方法的强大组合，为抗自诱导剂预防和治疗策略的产生、开发和评估提供坚实的合理基础。公共卫生相关性：我们研究中选择的细菌要么是对抗生素具有高度耐药性的新出现的病原体，因此在临床环境中存在问题，要么是潜在的生物恐怖主义和生物软件制剂。它们已被证明利用细菌细胞间的通讯（也称为“群体感应”）来控制其毒力。这些细菌用于通讯的分子代表了抗感染治疗的一个有吸引力的目标，因为清除这些小化合物将使细菌变得无害。此外，这些分子还会破坏宿主的免疫系统，从而使微生物首先建立感染。我们建议开发抗体来破坏细菌群体感应，从而制定对抗细菌感染的新策略。