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C-terminal proteolysis in the Pseudomonas aeruginosa cell envelope

铜绿假单胞菌细胞包膜中的 C 末端蛋白水解

基本信息

批准号：
10319533
负责人：
ANDREW J. DARWIN
金额：
$ 60.6万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319533
关键词：
Acceleration Acute Pneumonia Address Affect Alginates Antibiotic Resistance Attenuated Bacteria Binding Biochemical C-terminal Cell Wall Cells Clinical Complex Data Disease Disease Outbreaks Drug Targeting Enzymes Escherichia coli Family Goals Gram-Positive Bacteria Health Homologous Protein Hospitalization Hospitals Host Defense Human Immune system In Vitro Infection Intensive Care Units Knowledge Life Link Lipoprotein Binding Lipoproteins Membrane Metabolism Modification Molecular Multi-Drug Resistance N-Acetylmuramoyl-L-alanine Amidase Names Organism Patients Peptide Hydrolases Peptidoglycan Pharmaceutical Preparations Phenotype Polysaccharides Probability Production Prognosis Protein Export Pathway Proteins Proteolysis Pseudomonas aeruginosa Pseudomonas aeruginosa infection Reporting Research Resolution Role Sepsis Structure Surface System Testing Type III Secretion System Pathway Virulence Work Wound Infection acute infection cell envelope crosslink cystic fibrosis patients env Gene Products extracellular human pathogen in vivo insight lung colonization mouse model mutant new therapeutic target novel pathogen resistant strain scaffold severe burns targeted treatment

项目摘要

PROJECT SUMMARY The bacterium Pseudomonas aeruginosa is a common opportunistic human pathogen that causes life- threatening illnesses, including acute pneumonia, long-term lung colonization in most cystic fibrosis patients, and severe wound infections, especially in hospitalized patients and those with severe burns. Most P. aeruginosa infections are associated with compromised host defense and this, together with the common environmental occurrence of the organism, makes it a frequent cause of sepsis in the intensive care unit. The resolution of P. aeruginosa disease is challenging, in part because of its intrinsic resistance to antibiotics as well as occasional outbreaks of multi-drug-resistant strains in hospitals. Therefore, there is an urgent need to identify new targets for therapeutic attack. The cell envelope of P. aeruginosa has two C-terminal processing proteases or CTPs (named CtpA and Prc), both of which have been linked to systems associated with disease. In fact, many bacterial CTPs have been linked to virulence but very little is known about the underlying mechanisms. In P. aeruginosa, CtpA is essential for protein export by a machine known as a type 3 secretion system, one of the most important virulence systems for acute infections. Prc has been linked to a regulatory system that controls the production of a surface molecule known as alginate, which is associated with a poor prognosis in cystic fibrosis patients. We have now discovered that CtpA forms a complex with an uncharacterized outer membrane lipoprotein, which facilitates its activity. This proteolytic complex targets at least one enzyme that modifies the bacterial cell wall. We hypothesize that many other bacterial CTPs, including Prc in P. aeruginosa, will also work with partner proteins to target cell wall modifying enzymes, which makes an understanding of how these proteolytic complexes function broadly significant. Therefore, in this work we will: (1) Analyze how the lipoprotein partner facilitates CtpA-dependent proteolysis; (2), Investigate the impact of a CtpA substrate on the cell wall and virulence, and how its proteolysis is controlled within the bacterial cell; (3) Broaden the impact of this work by characterizing additional CtpA substrates and testing our hypothesis that Prc functions similarly. We predict that CTPs will emerge as a conserved mechanism by which bacteria regulate some of their cell wall modifying enzymes. Therefore, not only will this work provide insight into how CTPs function, which will be of relevance to many pathogens, but it will also shed light on how bacteria control the metabolism of one of their most clinically important components, the cell wall. Finally, the accessible cell envelope proteins that we characterize here could eventually be considered as new targets for therapeutic drugs.

项目摘要铜绿假单胞菌是一种常见的人类机会致病菌，威胁性疾病，包括急性肺炎，大多数囊性纤维化患者的长期肺定植，和严重的伤口感染，特别是在住院病人和严重烧伤的病人中。大多数P。铜绿假单胞菌感染与宿主防御受损有关，这与常见的微生物的环境发生，使其成为重症监护病房中败血症的常见原因。的铜绿假单胞菌疾病的解决是具有挑战性的，部分原因是其对抗生素的内在耐药性医院里偶尔爆发的多重耐药菌株。因此，迫切需要确定治疗攻击的新目标。铜绿假单胞菌的细胞被膜具有两个C-末端加工蛋白酶或CTP（命名为CtpA和Prc），两者都与疾病相关的系统有关。事实上，许多细菌CTP与毒力有关，但对潜在的机制知之甚少。在 p. CtpA对于蛋白质通过被称为3型分泌系统的机器输出是必需的，3型分泌系统是铜绿假单胞菌中的一种。最重要的毒力系统。PRC与一个监管体系相联系，一种称为藻酸盐的表面分子的产生，这与囊性癌的预后不良有关。纤维化患者我们现在已经发现CtpA与一个未知的外膜形成一个复合物脂蛋白，促进其活性。这种蛋白水解复合物靶向至少一种修饰蛋白水解酶的酶。细菌细胞壁我们假设许多其他细菌CTP，包括铜绿假单胞菌中的Prc，也将与伴侣蛋白质一起靶向细胞壁修饰酶，这使得人们了解这些蛋白质是如何作用于细胞壁的。蛋白水解复合物的功能广泛重要。因此，在这项工作中，我们将：（1）分析如何脂蛋白伴侣促进CtpA依赖性蛋白水解;（2），研究CtpA底物对CtpA依赖性蛋白水解的影响。细胞壁和毒力，以及如何在细菌细胞内控制其蛋白水解;（3）详述这项工作通过表征额外的CtpA底物和测试我们的假设，Prc功能相似。我们预测CTP将成为细菌调节部分细胞壁的保守机制修饰酶因此，这项工作不仅将提供深入了解现金转拨方案如何运作，这将是与许多病原体相关，但它也将揭示细菌如何控制它们的一种代谢。临床上最重要的成分细胞壁最后，我们发现的可接近的细胞包膜蛋白在这里描述的特征最终可以被认为是治疗药物的新靶点。