Bacterial cell killing by topoisomerase I mediated DNA lesion

拓扑异构酶 I 介导的 DNA 损伤杀死细菌细胞

基本信息

  • 批准号:
    8186092
  • 负责人:
  • 金额:
    $ 40.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-02-01 至 2012-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): This project targets bacterial type IA topoisomerase for discovery of novel antibacterial drugs as countermeasure for multi-drug resistant bacterial pathogens, including gram negatives. Drugs that initiate cell killing by trapping the covalent cleavage complex formed by type IB and type IIA topoisomerases are widely used in current anti-cancer and anti-bacterial therapy. Accumulation of type IA topoisomerase cleavage complex can trigger rapid bacterial cell death via the oxidative cell death pathway but specific inhibitors of type IA bacterial topoisomerase I that can be developed into new antibacterial drugs remain to be discovered. The proposed research activities for the next funding period would develop and utilize rapid cell based applicable for HTS assay format to identify small molecule compounds that have antibacterial activity due to specific interaction with bacterial topoisomerase I. Inhibitors of bacterial topoisomerase I identified from screening would be analyzed biochemically for mechanism of action and structure activity relationship. Priority would be given to compounds with low toxicity that are active against gram negative Escherichia coli and Yersinia pestis in order to identify leads that can be used in development of therapeutic agents against gram negative pathogens. Bacterial proteins that process trapped topoisomerase cleavage complexes will be identified with genetic and biochemical experiments. The repair proteins involved may be useful new targets for combination therapy with antibiotics targeting both type IA and type IIA topoisomerases. Success in these proposed experiments would provide tools and leads for development of novel antibacterial drugs for the urgent public health problem of bacterial pathogens resistant to all current antibiotics. PUBLIC HEALTH RELEVANCE: This project targets bacterial topoisomerase I enzyme for discovery of specific inhibitors. The proposed work would greatly aid the development of new antibacterial compounds against a novel target as part of the much needed arsenal to combat the global health problem of multi-drug drug resistant bacterial pathogens, including gram negatives.
描述(由申请人提供):本项目针对细菌IA型拓扑异构酶,用于发现新型抗菌药物,作为多重耐药细菌病原体(包括革兰氏阴性菌)的对策。通过捕获由IB型和IIA型拓扑异构酶形成的共价切割复合物来启动细胞杀伤的药物广泛用于当前的抗癌和抗菌治疗。IA型拓扑异构酶切割复合物的积累可以通过氧化细胞死亡途径引发细菌细胞快速死亡,但可以开发成新抗菌药物的IA型细菌拓扑异构酶I的特异性抑制剂仍有待发现。下一个资助期的拟议研究活动将开发和利用适用于HTS测定形式的快速细胞,以鉴定由于与细菌拓扑异构酶I的特异性相互作用而具有抗菌活性的小分子化合物。对筛选出的拓扑异构酶I抑制剂进行生物化学分析,探讨其作用机制和构效关系。将优先考虑对革兰氏阴性大肠杆菌和鼠疫耶尔森氏菌有活性的低毒性化合物,以确定可用于开发针对革兰氏阴性病原体的治疗剂的先导物。将通过遗传学和生物化学实验来鉴定处理捕获的拓扑异构酶切割复合物的细菌蛋白。所涉及的修复蛋白可能是有用的新靶标,用于与针对IA型和IIA型拓扑异构酶的抗生素联合治疗。这些拟议实验的成功将为开发新型抗菌药物提供工具和线索,以解决细菌病原体对所有现有抗生素耐药的紧迫公共卫生问题。 公共卫生相关性:该项目针对细菌拓扑异构酶I酶,以发现特异性抑制剂。拟议的工作将极大地帮助开发针对新目标的新抗菌化合物,作为急需的武器库的一部分,以应对包括革兰氏阴性菌在内的多药耐药细菌病原体的全球健康问题。

项目成果

期刊论文数量(0)
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Yuk-Ching Tse-Dinh其他文献

Yuk-Ching Tse-Dinh的其他文献

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{{ truncateString('Yuk-Ching Tse-Dinh', 18)}}的其他基金

Structure, Mechanism and Interactions of Type IA Topoisomerases
IA型拓扑异构酶的结构、机制和相互作用
  • 批准号:
    10389425
  • 财政年份:
    2021
  • 资助金额:
    $ 40.25万
  • 项目类别:
Structure, Mechanism and Interactions of Type IA Topoisomerases
IA型拓扑异构酶的结构、机制和相互作用
  • 批准号:
    10093404
  • 财政年份:
    2021
  • 资助金额:
    $ 40.25万
  • 项目类别:
Structure, Mechanism and Interactions of Type IA Topoisomerases
IA型拓扑异构酶的结构、机制和相互作用
  • 批准号:
    10569676
  • 财政年份:
    2021
  • 资助金额:
    $ 40.25万
  • 项目类别:
HTS assay development targeting Yersinia pestis topoisomerase I
针对鼠疫耶尔森菌拓扑异构酶 I 的 HTS 检测开发
  • 批准号:
    8234706
  • 财政年份:
    2010
  • 资助金额:
    $ 40.25万
  • 项目类别:
HTS assay development targeting Yersinia pestis topoisomerase I
针对鼠疫耶尔森菌拓扑异构酶 I 的 HTS 检测开发
  • 批准号:
    7991064
  • 财政年份:
    2010
  • 资助金额:
    $ 40.25万
  • 项目类别:
Bacterial cell killing by topoisomerase I mediated DNA lesion
拓扑异构酶 I 介导的 DNA 损伤杀死细菌细胞
  • 批准号:
    8070106
  • 财政年份:
    2010
  • 资助金额:
    $ 40.25万
  • 项目类别:
Bacterial cell killing by topoisomerase I mediated DNA lesion
拓扑异构酶 I 介导的 DNA 损伤杀死细菌细胞
  • 批准号:
    7756650
  • 财政年份:
    2006
  • 资助金额:
    $ 40.25万
  • 项目类别:
Bacterial cell killing by topoisomerase I mediated DNA lesion
拓扑异构酶 I 介导的 DNA 损伤杀死细菌细胞
  • 批准号:
    7169238
  • 财政年份:
    2006
  • 资助金额:
    $ 40.25万
  • 项目类别:
Bacterial cell killing topoisomerase I--DNA lesion
细菌细胞杀伤拓扑异构酶I--DNA损伤
  • 批准号:
    7083065
  • 财政年份:
    2006
  • 资助金额:
    $ 40.25万
  • 项目类别:
Bacterial cell killing by topoisomerase I mediated DNA lesion
拓扑异构酶 I 介导的 DNA 损伤杀死细菌细胞
  • 批准号:
    7333269
  • 财政年份:
    2006
  • 资助金额:
    $ 40.25万
  • 项目类别:

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