Novel Antimicrobials Targeting Cell Division

针对细胞分裂的新型抗菌剂

基本信息

  • 批准号:
    7994775
  • 负责人:
  • 金额:
    $ 37.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-12-01 至 2013-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): It is evident that the widespread misuse of antimicrobial drugs has caused bacterial resistance to all classes of antibiotics. At present, one of the most serious problems worldwide is the multi-drug resistant tuberculosis (MDR-TB), which is classified as an emerging infectious disease threat and a category C priority pathogen by NIAID/NIH. In addition, the recent emergence of extensively drug resistant strains of TB (XDR-TB) that are resistant to both first and second line drugs is even more alarming. Another threat is the infections due to drug-resistant Enterococci (VRE) and Staphylococcus aureus (MRSA), which are serious problems in hospitalized or immunocompromised individuals. There has been a rapid increase in the incidence of VRE infections, as well as a dramatic increase in the incidence of MRSA infections. Unfortunately, at present, there are only very limited therapeutic options available for patients with these infections. Therefore, there is an urgent need for the development of novel antimicrobials against new targets essential for growth, whose inhibition should give a lethal phenotype. Thus, we have selected FtsZ, the tubulin homologue in bacterial cells and essential to bacterial cell division, as the specific target to develop a new class of antimicrobial agents. The bacterial tubulin homologue FtsZ is an essential cell-division protein in bacteria that polymerizes in a GTP-dependent manner, forming a cytokinetic ring at the septum site. Accordingly, FtsZ is a very promising target for discovery and development of new broad-spectrum antimicrobial drugs because of its central role in bacterial cell division. The Principal Investigator (PI) has expertise in anticancer agents targeting tubulin/microtubules and has hypothesized that a certain class of taxanes (microtubule-stabilizer) and benzimidazoles (tubulin polymerization inhibitors) should inhibit the depolymerization or polymerization of FtsZ from Mycobacterium tuberculosis (MTB), MRSA and VRE. The fact that the sequence homology between FtsZ and tubulin is low (<20% identity) strongly indicates an excellent possibility in discovering FtsZ-specific taxanes and benzimidazoles that are non-cytotoxic to human host cells. Building upon highly encouraging preliminary results, the following specific aims will be investigated: (1) Design, Synthesis, Screening and Optimization of Taxanes and Benzimidazoles (2) Investigation into the Mechanism of Action in vitro (3) Investigation into the Mechanism of Action in Live Cells (4) In vivo Efficacy Evaluation with Animal Models Highly integrated collaborative activities will be performed through close cooperation between the Institute for Chemical Biology and Drug Discovery (ICB&DD) at Stony Brook University and The Mycobacteriology Laboratory at Colorado State University. PUBLIC HEALTH RELEVANCE: Multi-drug resistant and extensively drug resistant tuberculosis (MDR-TB and XDR-TB) are classified as an emerging infectious disease threat and category C priority pathogens by NIAID/NIH. Another emerging threat is the infections due to drug-resistant Staphylococcus aureus (MRSA) and Enterococci (VRE), which are serious problems in hospitalized or immunocompromised individuals. Unfortunately, at present, there are only very limited therapeutic options available for patients with these infections. Therefore, there is an urgent need for the development of novel antimicrobials against new targets essential for growth, whose inhibition should give a lethal phenotype. Thus, we have selected FtsZ, the tubulin homologue in bacterial cells and essential to bacterial cell division, as the specific target to develop a new class of antimicrobial agents.
描述(由申请人提供):很明显,抗菌药物的广泛滥用已导致细菌对所有类别的抗生素产生耐药性。耐多药结核病(MDR-TB)是目前世界范围内最严重的问题之一,被NIAID/NIH列为C类优先病原体,是一种新出现的传染病威胁。此外,最近出现的对一线和二线药物都有抗药性的广泛耐药结核菌株甚至更令人震惊。另一个威胁是由耐药肠球菌(VRE)和金黄色葡萄球菌(MRSA)引起的感染,这是住院或免疫功能低下的个体的严重问题。VRE感染的发病率迅速增加,MRSA感染的发病率也急剧增加。不幸的是,目前,只有非常有限的治疗选择可用于这些感染的患者。因此,迫切需要开发针对生长所必需的新靶标的新型抗菌剂,其抑制应产生致死表型。因此,我们选择了FtsZ,微管蛋白同源物在细菌细胞和细菌细胞分裂所必需的,作为特定的目标,开发一类新的抗菌剂。细菌微管蛋白同源物FtsZ是细菌中以GTP依赖性方式聚合的必需细胞分裂蛋白,在隔膜位点形成细胞动力学环。因此,FtsZ是一个非常有前途的目标,发现和开发新的广谱抗菌药物,因为它在细菌细胞分裂的核心作用。主要研究者(PI)具有靶向微管蛋白/微管的抗癌药物的专业知识,并假设某类紫杉烷(微管稳定剂)和苯并咪唑(微管蛋白聚合抑制剂)应抑制结核分枝杆菌(MTB)、MRSA和VRE中FtsZ的解聚或聚合。FtsZ和微管蛋白之间的序列同源性低(<20%同一性)的事实强烈表明发现对人宿主细胞无细胞毒性的FtsZ特异性紫杉烷和苯并咪唑的极好可能性。在非常令人鼓舞的初步结果的基础上,将研究以下具体目标:(1)设计、合成、紫杉烷类和苯并咪唑类药物的筛选和优化(2)体外作用机制研究(3)活细胞作用机制研究(4)使用动物模型的体内疗效评价将通过研究所与以下机构之间的密切合作进行高度整合的合作活动:斯托尼布鲁克大学的化学生物学和药物发现(ICB&DD)和科罗拉多州立大学的分枝杆菌学实验室。 公共卫生关系:耐多药和广泛耐药结核病(MDR-TB和XDR-TB)被NIAID/NIH列为新出现的传染病威胁和C类优先病原体。另一个新出现的威胁是由耐药金黄色葡萄球菌(MRSA)和肠球菌(VRE)引起的感染,这是住院或免疫功能低下个体的严重问题。不幸的是,目前,只有非常有限的治疗选择可用于这些感染的患者。因此,迫切需要开发针对生长所必需的新靶标的新型抗菌剂,其抑制应产生致死表型。因此,我们选择了FtsZ,微管蛋白同源物在细菌细胞和细菌细胞分裂所必需的,作为特定的目标,开发一类新的抗菌剂。

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(2)

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IWAO OJIMA其他文献

IWAO OJIMA的其他文献

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{{ truncateString('IWAO OJIMA', 18)}}的其他基金

Novel Antimicrobials Targeting Cell Division
针对细胞分裂的新型抗菌剂
  • 批准号:
    8196969
  • 财政年份:
    2008
  • 资助金额:
    $ 37.63万
  • 项目类别:
Novel Antimicrobials Targeting Cell Division
针对细胞分裂的新型抗菌剂
  • 批准号:
    7739500
  • 财政年份:
    2008
  • 资助金额:
    $ 37.63万
  • 项目类别:
Novel Antimicrobials Targeting Cell Division
针对细胞分裂的新型抗菌剂
  • 批准号:
    8389654
  • 财政年份:
    2008
  • 资助金额:
    $ 37.63万
  • 项目类别:
Novel Antimicrobials Targeting Cell Division
针对细胞分裂的新型抗菌剂
  • 批准号:
    7583683
  • 财政年份:
    2008
  • 资助金额:
    $ 37.63万
  • 项目类别:
Drug Discovery & Biodiversity Conservation in Madagascar
药物发现
  • 批准号:
    6805213
  • 财政年份:
    2003
  • 资助金额:
    $ 37.63万
  • 项目类别:
Drug Discovery & Biodiversity Conservation in Madagascar
药物发现
  • 批准号:
    6711934
  • 财政年份:
    2003
  • 资助金额:
    $ 37.63万
  • 项目类别:
Taxane and Taxoid Chemotherapeutic Agents
紫杉烷和紫杉烷类化疗药物
  • 批准号:
    7092254
  • 财政年份:
    1990
  • 资助金额:
    $ 37.63万
  • 项目类别:
Taxane and Taxoid Chemotherapeutic Agents
紫杉烷和紫杉烷类化疗药物
  • 批准号:
    6781078
  • 财政年份:
    1990
  • 资助金额:
    $ 37.63万
  • 项目类别:
NON-PROTEIN AMINO ACIDS AND TAXOID ANTITUMOR AGENTS
非蛋白质氨基酸和紫杉烷抗肿瘤剂
  • 批准号:
    2900722
  • 财政年份:
    1990
  • 资助金额:
    $ 37.63万
  • 项目类别:
NON-PROTEIN AMINO ACIDS AND TAXOID ANTITUMOR AGENTS
非蛋白质氨基酸和紫杉烷抗肿瘤剂
  • 批准号:
    6571509
  • 财政年份:
    1990
  • 资助金额:
    $ 37.63万
  • 项目类别:

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  • 批准号:
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  • 财政年份:
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  • 财政年份:
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  • 资助金额:
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