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

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.
项目总结

项目成果

期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A Proteolytic Complex Targets Multiple Cell Wall Hydrolases in Pseudomonas aeruginosa.
  • DOI:
    10.1128/mbio.00972-18
  • 发表时间:
    2018-07-17
  • 期刊:
  • 影响因子:
    6.4
  • 作者:
    Srivastava D;Seo J;Rimal B;Kim SJ;Zhen S;Darwin AJ
  • 通讯作者:
    Darwin AJ
Pseudomonas aeruginosa C-Terminal Processing Protease CtpA Assembles into a Hexameric Structure That Requires Activation by a Spiral-Shaped Lipoprotein-Binding Partner.
  • DOI:
    10.1128/mbio.03680-21
  • 发表时间:
    2022-02-22
  • 期刊:
  • 影响因子:
    6.4
  • 作者:
    Hsu HC;Wang M;Kovach A;Darwin AJ;Li H
  • 通讯作者:
    Li H
An inhibitor/anti-inhibitor system controls the activity of lytic transglycosylase MltF in Pseudomonas aeruginosa.
  • DOI:
    10.1128/mbio.02022-23
  • 发表时间:
    2023-12-19
  • 期刊:
  • 影响因子:
    6.4
  • 作者:
  • 通讯作者:
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ANDREW J. DARWIN其他文献

ANDREW J. DARWIN的其他文献

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{{ truncateString('ANDREW J. DARWIN', 18)}}的其他基金

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
  • 批准号:
    10312116
  • 财政年份:
    2020
  • 资助金额:
    $ 60.6万
  • 项目类别:
The Pseudomonas aeruginosa protease CtpA and type 3 secretion
铜绿假单胞菌蛋白酶CtpA和3型分泌
  • 批准号:
    8995635
  • 财政年份:
    2015
  • 资助金额:
    $ 60.6万
  • 项目类别:
The Psp response of Yersinia enterocolitica
小肠结肠炎耶尔森氏菌的 Psp 反应
  • 批准号:
    6717703
  • 财政年份:
    2003
  • 资助金额:
    $ 60.6万
  • 项目类别:
The Psp response of Yersinia enterocolitica
小肠结肠炎耶尔森氏菌的 Psp 反应
  • 批准号:
    8215878
  • 财政年份:
    2003
  • 资助金额:
    $ 60.6万
  • 项目类别:
The Psp response of Yersinia enterocolitica
小肠结肠炎耶尔森氏菌的 Psp 反应
  • 批准号:
    8241198
  • 财政年份:
    2003
  • 资助金额:
    $ 60.6万
  • 项目类别:
The Psp response of Yersina enterocolitica
小肠结肠炎耶尔森氏菌的 Psp 反应
  • 批准号:
    8695130
  • 财政年份:
    2003
  • 资助金额:
    $ 60.6万
  • 项目类别:
The Psp response of Yersinia enterocolitica
小肠结肠炎耶尔森氏菌的 Psp 反应
  • 批准号:
    8418767
  • 财政年份:
    2003
  • 资助金额:
    $ 60.6万
  • 项目类别:
The Psp response of Yersina enterocolitica
小肠结肠炎耶尔森氏菌的 Psp 反应
  • 批准号:
    9258378
  • 财政年份:
    2003
  • 资助金额:
    $ 60.6万
  • 项目类别:
The Psp response of Yersinia enterocolitica
小肠结肠炎耶尔森氏菌的 Psp 反应
  • 批准号:
    7650987
  • 财政年份:
    2003
  • 资助金额:
    $ 60.6万
  • 项目类别:
The Psp response of Yersinia enterocolitica
小肠结肠炎耶尔森氏菌的 Psp 反应
  • 批准号:
    7186637
  • 财政年份:
    2003
  • 资助金额:
    $ 60.6万
  • 项目类别:

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Point-of-care infection identification system in 30 minutes - tackling acute pneumonia in emergency rooms and intensive care units
30分钟的床旁感染识别系统——应对急诊室和重症监护室的急性肺炎
  • 批准号:
    10076451
  • 财政年份:
    2023
  • 资助金额:
    $ 60.6万
  • 项目类别:
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