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

• 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
• 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

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.

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.这些革兰氏阴性细菌（baumannii除外）是A类（Y. Pestis）和B（B. pseudomallei和B. mallei）选择的病原体，被指定为指定，因此很可能在生物恐怖主义或生物群的事件中使用。虽然潜在的不如其他A和B类病原体那样致命，但它们仍然构成显着的发病率威胁，如果通过气溶胶传递，则具有高感染性潜力。目前，针对此类细菌感染的FDA批准疗法的数量仅限于两到三种抗生素，并且全部仅具有暴露后的指示。此外，通过引入已知抗性因子，可以轻松地使基于抗生素的治疗无效。因此，制定替代性抗感染策略以保护这些病原体是很重要的。另一方面，鲍曼尼曲霉正成为医院感染中常见的多药耐药性病原体，以及在伊拉克和阿富汗战场上在美国士兵中看到的伤口感染的日益严重的威胁。 所有为这些研究选择的病原体都已证明使用细菌细胞对细胞通信，也称为“ Quorum Sensing”。最近，我们和其他人表明，细菌QS系统代表了预防性和治疗性干预的有吸引力的靶标。 QS信号传导基于较小的扩散分子的交换，例如N-酰基同素内酯（AHL），这些分子实际上是由A. Baumannii，B。Mallei，B。Pseudomallei和Y. Pestis使用的。类似于经典病原体相关的分子模式（PAMP），例如细菌脂多糖（LPS）和肽聚糖，AHL仅由微生物病原体产生，而不是由哺乳动物宿主产生的。最近的研究表明，基于AHL的QS分子对巨噬细胞发挥有效的细胞毒性，这表明AHL在拆除宿主先天免疫中的额外作用。申请人进行的研究提供了进一步的证据，表明AHL直接激活包括白细胞在内的哺乳动物细胞中的信号传导事件，并且这些事件是通过与经典PAMP识别受体（PRR）途径不同的机制发生的，例如规范性Toll-toll-like受体（TLR）和NOD-LI-LI-LI-LI-LI-LI-LI-LI-LI-LI-LIKE受体（NLR）途径。因此，除了它们在细菌交流中的作用外，AHL自动诱导剂本身可能代表了抗感染免疫疗法的新目标。在该提议中，将利用化学，分子生物学，免疫学和遗传方法的有力结合，为抗自动诱导者预防和治疗策略的产生，发展和评估提供可靠的合理基础。 公共卫生相关性：为我们的研究选择的细菌要么是具有高度抗生素耐药性的新的新兴病原体，因此在临床环境中有问题，或者是潜在的生物恐怖主义和生物疗法剂。已显示它们利用细菌细胞对细胞的通信，也称为“法定感应”来控制其毒力。这些细菌用于交流的分子代表了抗感染治疗的有吸引力的靶标，因为清除小型化合物会使细菌无害。此外，这些分子还颠覆了宿主免疫系统，因此使微生物首先建立了它们的感染。我们建议开发抗体，以破坏细菌群体的传感，从而制定与细菌感染作斗争的新策略。