权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting bacterial phosphatases for novel anti-bacterial agents.

针对细菌磷酸酶的新型抗菌剂。

基本信息

批准号：
8298885
负责人：
Maurizio Pellecchia
金额：
$ 24.38万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8298885
关键词：
Adjuvant Anti-Bacterial Agents Antibiotics Antibodies Antigens B-Lymphocytes Bacteria Bacterial Antigens Bacterial Proteins Bacterial Toxins Biological Assay Categories Cause of Death Cell Death Cell Death Inhibition Cells Complement Computer Simulation Cytoskeleton Development Disease Docking Doctor of Philosophy Drug Kinetics Ensure Eukaryotic Cell Failure Focal Adhesions Generations Gentamicins Goals Human Immune Immune response Immune system In Vitro Infection Integrin Inhibition Mediating Molecular Molecular Probes Multi-Drug Resistance Mus Paralysed Phagocytes Phagocytosis Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phosphoric Monoester Hydrolases Pilot Projects Plasmids Play Point Mutation Production Property Protein Tyrosine Kinase Protein Tyrosine Phosphatase Proteins Receptor Signaling Role Salmonella enterica Screening procedure Series Signal Transduction Staging Structure T-Lymphocyte Technology Therapeutic Toxin Type III Secretion System Pathway Tyrosine Phosphorylation Virulence Virulence Factors Virulent Work Yersinia Yersinia enterocolitica Yersinia pestis base drug candidate efficacy testing experience fighting human disease in vivo inhibitor/antagonist innovation killings lymph nodes macrophage novel pathogen phosphatase inhibitor prevent salicylate small molecule small molecule libraries stem

项目摘要

DESCRIPTION (provided by applicant): Yersinia pestis, Salmonella enterica, and Yersinia enterocolitica use a number of toxins to evade the immune system one of which is the protein tyrosine phosphatase YopH. Following infection, YopH is injected into phagocytic cell resulting in the disruption of focal adhesions, and inhibition of integrin-mediated bacterial phagocytosis, both of which are highly dependent on tyrosine phosphorylation. Hence, targeting YopH against these pathogens represents a sensible yet underexplored strategy for the development of novel anti-bacterial adjuvant to antibiotics. Our hypothesis is that effective small-molecule inhibitors f YopH would render YopH- paralyzed immune cells immediately functional again hence able to initiate both innate and adaptive immune responses. Hence, the molecules that will arise from this pilot study may result very useful not only as potential therapeutics, but also in probing at the cellular level the mechanisms of toxin induced cell death and inhibition of phagocytosis, common to several other pathogens. PUBLIC HEALTH RELEVANCE: We envision that inhibitors of a critical bacterial toxin may be valuable for treating Yersinia pestis, Salmonella enterica, and Yersinia enterocolitica infections, as a supportive complement to antibiotics. This pilot study will provide critical proof of concept for this innovative approach.

描述（由申请方提供）：鼠疫耶尔森菌、肠道沙门氏菌和小肠结肠炎耶尔森菌使用多种毒素逃避免疫系统，其中一种是蛋白酪氨酸磷酸酶YopH。感染后，将YopH注射到吞噬细胞中，导致粘着斑的破坏和整联蛋白介导的细菌吞噬作用的抑制，这两者都高度依赖于酪氨酸磷酸化。因此，针对这些病原体靶向YopH代表了用于开发抗生素的新型抗菌佐剂的合理但未充分探索的策略。我们的假设是有效的YopH小分子抑制剂将使YopH麻痹的免疫细胞立即再次发挥功能，因此能够启动先天性和适应性免疫应答。因此，从这个试点研究中产生的分子可能不仅作为潜在的治疗剂非常有用，而且在细胞水平上探测毒素诱导的细胞死亡和抑制吞噬作用的机制，常见的几种其他病原体。公共卫生相关性：我们设想关键细菌毒素的抑制剂可能对治疗鼠疫耶尔森氏菌、肠道沙门氏菌和小肠结肠炎耶尔森氏菌感染有价值，作为抗生素的辅助补充这项试点研究将为这一创新方法提供关键的概念证明。