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The roles of the Pseudomonas aeruginosa Prc/AlgO protease - Resubmission - 1

铜绿假单胞菌 Prc/AlgO 蛋白酶的作用 - 重新提交 - 1

基本信息

批准号：
10312116
负责人：
ANDREW J. DARWIN
金额：
$ 21.19万
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：
2020
资助国家：
美国
起止时间：
2020-12-07 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10312116
关键词：
Acute Pneumonia Address Adopted Affect Alginates Anabolism Antibiotic Resistance Antibiotics Bacteria C-terminal Catalytic Domain Cell Wall Cells Cystic Fibrosis Dangerousness Data Development Disease Disease Outbreaks Drug Targeting Enzymes Escherichia coli Funding Future Goals Health Host Defense Human Hydrolase Immune system Individual Infection Life Link Metabolism Modeling Multi-Drug Resistance N-Acetylmuramoyl-L-alanine Amidase N-terminal Names Nosocomial Infections Patients Peptide Hydrolases Peptidoglycan Phenotype Play Polysaccharides Process Production Prognosis Proteins Pseudomonas aeruginosa Regulation Regulon Research Role Sigma Factor Testing Therapeutic Intervention Virulence Work Wound Infection acute infection cell envelope cell growth chronic infection cleavage factor cost crosslink cystic fibrosis patients extracellular genetic regulatory protein human pathogen insight lung colonization mucoid new therapeutic target novel novel therapeutic intervention pathogen pathogenic bacteria periplasm resistant strain targeted treatment therapeutic target

项目摘要

PROJECT SUMMARY The bacterial pathogen Pseudomonas aeruginosa causes life-threatening human illnesses, including acute pneumonia, long-term lung colonization in cystic fibrosis patients, and severe wound infections. Most infections are associated with compromised host defenses and this, together with the common environmental occurrence of P. aeruginosa, makes it a leading cause of hospital-acquired infections. Treatment of P. aeruginosa disease is often challenging, in part because of its intrinsic resistance to antibiotics as well as occasional outbreaks of multi-drug-resistant strains. Therefore, there is an urgent need to characterize new targets for therapeutic attack. The P. aeruginosa cell envelope contains a C-terminal processing protease (CTP) named CtpA, which is essential for acute infection. CtpA has adopted a similar role to that of the only CTP found in Escherichia coli, Prc, even though CtpA and Prc are quite different from each other. Both CtpA in P. aeruginosa, and Prc in E. coli, degrade enzymes that remodel the bacterial cell wall. This is intriguing because whereas many bacteria like E. coli have only one CTP, P. aeruginosa has two, and the second one is named Prc because it is very similar to E. coli Prc. This raises the new question for this exploratory/developmental proposal: if CtpA achieves the role played by Prc in E. coli, then what does Prc do in Pa? Prc has been proposed to cleave the negative regulatory protein MucA, triggering extracellular polysaccharide production and a phenotype associated with a poor prognosis in cystic fibrosis patients. However, neither MucA or any other P. aeruginosa protein has been demonstrated to be a Prc substrate. From our preliminary data, we are proposing an exciting new model for the differential control of at least one PG cross-link hydrolase by both Prc and CtpA. Together with our other observations suggesting that Prc affects the cell wall, this supports our central hypothesis, which is that Prc cleaves important proteins involved in cell wall metabolism, and that this might have an indirect impact on the cleavage of the anti-sigma factor MucA. To test this hypothesis, we will: (1) Determine if Prc and CtpA play different roles in degrading common substrates and (2) Establish how Prc affects alginate regulation and the mucoid conversion phenotype. This work will impact our understanding of fundamental, conserved processes important to almost all bacteria. It will also provide the first clear insight into exactly what Prc does in Pa, and the mechanism(s) by which it affects alginate biosynthesis, mucoid conversion, and cell wall features that impact human health. Understanding these mechanisms might ultimately help the development of new therapeutic strategies against this widespread, dangerous and very costly human pathogen.

项目总结