Novel antimicrobials targeting type IV pilus and type 2 secretion systems

针对 IV 型菌毛和 2 型分泌系统的新型抗菌药物

基本信息

  • 批准号:
    9089860
  • 负责人:
  • 金额:
    $ 4.57万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-07-01 至 2016-10-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Bacterial pathogens have conserved complex molecular machines that are required to cause disease. Among these machines are those that make up a type IV pilus (T4P) biogenesis apparatus and the related type II secretion (T2S) machine. T4Ps are surface appendages essential for adherence and host colonization by many important bacterial pathogens; T2S systems export toxins that are critical for many diseases. Acinetobacter baumanii, Pseudomonas aeruginosa, and Neisseria gonorrhoeae all produce T4Ps. Among the components common to both machines is a pre-pilin peptidase enzyme that specifically removes the characteristic N-terminal signal sequence from pre-pilin proteins and N-methylates the nascent amino terminus. These enzymes are highly conserved, absolutely required for T4P and T2S function, and represent a novel class of neutral pH aspartic acid peptidases that do not resemble mammalian enzymes. As such, they are ideal targets for new drug discovery. We have devised an in vivo Föster resonance energy transfer (FRET) system comprised of three recombinant proteins expressed in E. coli: the pre-pilin peptidase, the pre-pilin protein fused to enhanced yellow fluorescent protein (eYFP), and an essential assembly protein to which the pre-pilin binds fused to dsRed. Cleavage of the pre-pilin fusion protein by the pre-pilin peptidase releases eYFP and prevents FRET with dsRed. If the pre-pilin peptidase is inactivated by mutation, then FRET occurs. We will adapt this extremely sensitive system and a related even simpler system that relies on fluorescence anisotropy to develop in vitro high-throughput small molecule screens to identify pre-pilin peptidase inhibitor candidates. Secondary assays will establish specificity and spectrum of activity. The initial effort will provie candidates that will subsequently subjected to further chemical refinement to enhance potency, specificity and activity against whole bacteria. Finally, (a) lead compound(s) will be advanced to preclinical testing using an established murine model of P. aeruginosa pneumonia in which T4Ps are required for disease. Ultimately, the goal is to discover an entirely novel therapeutic class of anti-virulence agents to improve human health.
 描述(由申请人提供):细菌病原体具有引起疾病所需的保守的复杂分子机器。这些机器包括构成 IV 型菌毛 (T4P) 生物发生装置和相关的 II 型分泌 (T2S) 机器的机器。 T4P 是许多重要细菌病原体粘附和宿主定殖所必需的表面附属物; T2S 系统输出对许多疾病至关重要的毒素。鲍曼不动杆菌、铜绿假单胞菌和淋病奈瑟菌均产生 T4P。这两种机器的共同组件之一是前菌毛蛋白肽酶,它特异性地从前菌毛蛋白中去除特征性的 N 末端信号序列,并对新生的氨基末端进行 N 甲基化。这些酶高度保守,是 T4P 和 T2S 功能所必需的,代表了一类新型的中性 pH 值天冬氨酸肽酶,与哺乳动物酶不同。因此,它们是新药发现的理想靶标。我们设计了一种体内 Föster 共振能量转移 (FRET) 系统,由在大肠杆菌中表达的三种重组蛋白组成:前菌毛蛋白肽酶、与增强型黄色荧光蛋白 (eYFP) 融合的前菌毛蛋白,以及与 dsRed 融合的前菌毛蛋白结合的必需组装蛋白。前菌毛蛋白肽酶对前菌毛蛋白融合蛋白的裂解释放 eYFP 并阻止 dsRed 的 FRET。如果前菌毛蛋白肽酶因突变而失活,则会发生 FRET。我们将采用这个极其敏感的系统和一个相关的更简单的系统,该系统依赖于荧光各向异性来开发体外高通量小分子筛选,以识别前菌毛蛋白肽酶抑制剂候选物。二次测定将确定活性的特异性和谱。最初的努力将提供候选物,随后将对其进行进一步的化学精制,以增强针对整个细菌的效力、特异性和活性。最后,(a)先导化合物将使用已建立的铜绿假单胞菌肺炎小鼠模型进行临床前测试,其中疾病需要 T4P。最终,我们的目标是发现一种全新的治疗类抗毒剂,以改善人类健康。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

MICHAEL S DONNENBERG其他文献

MICHAEL S DONNENBERG的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('MICHAEL S DONNENBERG', 18)}}的其他基金

VCU Medical Scientist Training Program
VCU 医学科学家培训计划
  • 批准号:
    10624225
  • 财政年份:
    2022
  • 资助金额:
    $ 4.57万
  • 项目类别:
VCU Medical Scientist Training Program
VCU 医学科学家培训计划
  • 批准号:
    10333929
  • 财政年份:
    2022
  • 资助金额:
    $ 4.57万
  • 项目类别:
VCU NIGMS Mentoring supplement
VCU NIGMS 指导补充
  • 批准号:
    10810342
  • 财政年份:
    2022
  • 资助金额:
    $ 4.57万
  • 项目类别:
Secretin Architecture
分泌素架构
  • 批准号:
    9245656
  • 财政年份:
    2016
  • 资助金额:
    $ 4.57万
  • 项目类别:
Secretin Architecture
分泌素架构
  • 批准号:
    9386875
  • 财政年份:
    2016
  • 资助金额:
    $ 4.57万
  • 项目类别:
Secretin Architecture
分泌素架构
  • 批准号:
    9092713
  • 财政年份:
    2016
  • 资助金额:
    $ 4.57万
  • 项目类别:
Novel antimicrobials targeting type IV pilus and type 2 secretion systems
针对 IV 型菌毛和 2 型分泌系统的新型抗菌药物
  • 批准号:
    8955922
  • 财政年份:
    2015
  • 资助金额:
    $ 4.57万
  • 项目类别:
Novel antimicrobials targeting type IV pilus and type 2 secretion systems
针对 IV 型菌毛和 2 型分泌系统的新型抗菌药物
  • 批准号:
    9386954
  • 财政年份:
    2015
  • 资助金额:
    $ 4.57万
  • 项目类别:
Pathogenesis
发病
  • 批准号:
    8683080
  • 财政年份:
    2014
  • 资助金额:
    $ 4.57万
  • 项目类别:
Structure and Role in Disease of Clostridium difficile Type IV Pili
艰难梭菌 IV 型菌毛的结构和在疾病中的作用
  • 批准号:
    8504227
  • 财政年份:
    2013
  • 资助金额:
    $ 4.57万
  • 项目类别:

相似海外基金

Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections
用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
  • 批准号:
    MR/Y008693/1
  • 财政年份:
    2024
  • 资助金额:
    $ 4.57万
  • 项目类别:
    Research Grant
Generative machine learning for narrow spectrum antibiotic discovery against Acinetobacter baumannii
生成机器学习用于发现针对鲍曼不动杆菌的窄谱抗生素
  • 批准号:
    477936
  • 财政年份:
    2023
  • 资助金额:
    $ 4.57万
  • 项目类别:
    Operating Grants
Conserved structural dynamics of outer-membrane channels in Acinetobacter baumannii as potential drug targets
鲍曼不动杆菌外膜通道的保守结构动力学作为潜在的药物靶点
  • 批准号:
    494854
  • 财政年份:
    2023
  • 资助金额:
    $ 4.57万
  • 项目类别:
    Operating Grants
Defining key players at the host-pathogen interface during Acinetobacter baumannii infection
定义鲍曼不动杆菌感染期间宿主-病原体界面的关键参与者
  • 批准号:
    488684
  • 财政年份:
    2023
  • 资助金额:
    $ 4.57万
  • 项目类别:
    Operating Grants
Study of clinically over-expressed and chimeric RND multidrug efflux pumps from Acinetobacter baumannii and Pseudomonas aeruginosa
鲍曼不动杆菌和铜绿假单胞菌临床过表达和嵌合 RND 多药外排泵的研究
  • 批准号:
    23K14346
  • 财政年份:
    2023
  • 资助金额:
    $ 4.57万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Biomimetic Macrophage Membrane-Coated Nanosponges: A Novel Therapeutic for Multidrug-Resistant Pseudomonas aeruginosa and Acinetobacter baumannii Hospital-Associated Pneumonia
仿生巨噬细胞膜包被的纳米海绵:一种治疗多重耐药铜绿假单胞菌和鲍曼不动杆菌医院相关肺炎的新疗法
  • 批准号:
    10674406
  • 财政年份:
    2023
  • 资助金额:
    $ 4.57万
  • 项目类别:
Using strain history to improve prediction of the evolution of antimicrobial resistance in Acinetobacter baumannii
利用菌株历史改进对鲍曼不动杆菌抗菌药物耐药性演变的预测
  • 批准号:
    10677362
  • 财政年份:
    2023
  • 资助金额:
    $ 4.57万
  • 项目类别:
Inhibitors of adaptive efflux mediated resistance in Acinetobacter baumannii
鲍曼不动杆菌适应性外排介导的耐药性抑制剂
  • 批准号:
    10625029
  • 财政年份:
    2023
  • 资助金额:
    $ 4.57万
  • 项目类别:
Identifying niche specific adaptations in Acinetobacter baumannii
鉴定鲍曼不动杆菌的生态位特异性适应
  • 批准号:
    10596620
  • 财政年份:
    2022
  • 资助金额:
    $ 4.57万
  • 项目类别:
Identifying niche specific adaptations in Acinetobacter baumannii
鉴定鲍曼不动杆菌的生态位特异性适应
  • 批准号:
    10449699
  • 财政年份:
    2022
  • 资助金额:
    $ 4.57万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了