HTS for bactericidal inhibitors of M. tuberculosis copper resistance mechanisms

HTS 用于结核分枝杆菌铜耐药机制的杀菌抑制剂

基本信息

  • 批准号:
    8480032
  • 负责人:
  • 金额:
    $ 34.07万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-02-20 至 2016-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): With > 1.4 million people dying every year from Mycobacterium tuberculosis (Mtb) infection, tuberculosis (TB) is considered a pandemic, which is increasingly difficult to control. The deadly synergy between TB and HIV infection, and the alarming number of drug-resistant Mtb strains threaten our ability to control TB, even in developed countries. To halt and reverse this development, novel therapeutics that dramatically shorten and simplify TB treatment and that use new drug targets are needed. We recently discovered copper homeostasis as an important virulence factor of Mtb. We can demonstrate that genetic perturbation of Mtb copper homeostasis induces copper hypersensitivity which is associated with a strong virulence defect. Copper ions are employed by macrophages to kill Mtb hence compounds that synergize with copper dependent innate immune functions create novel opportunities for therapeutic interference. In this project we will develop a robust combinatorial high-throughput screening (HTS) assay for the identification of copper-boosting drugs that either (i) inhibit individual components of (ii) or increase copper uptake and thereby overwhelm the intrinsic copper resistance pathways of Mtb. In Aim 1, we will optimize and transfer an HTS screening assay for copper-boosting drugs to a robotic platform utilizing a BSL2 approved mutant of Mtb H37Rv. In Aim 2, we will develop and validate novel and more rapid secondary assays, which will guide hit prioritization. In particular, we will validate and utilize a flow cytometry-based approach to evaluate viability of drug exposed avirulent Mtb cells. This assessment is 1,000 times faster than traditional CFU counts, is HTS compatible, supports kinetic read-outs and requires less than 1,000 individual cells per read and condition. The various assays are designed to test whether the identified hits act as bactericidal or bacteriostatic compounds, exhibit activity against latent (non-growing) Mtb or interact with antiretroviral drugs. In research leading to this application, we have already identified two proof of concept compounds that target Mtb in a copper dependent manner and exhibit an in vitro therapeutic index of >20. In Aim 3, we will perform a pilot screen to evaluate overall assay performance. Upon completion of this pilot campaign, we intend to apply for Fast Track entry of our screening assay into the NIH Molecular Libraries Probe Production Centers Network (Aim 4).
描述(由申请人提供):每年有超过140万人死于结核分枝杆菌(Mtb)感染,结核病(TB)被认为是一种流行病,越来越难以控制。结核病和艾滋病毒感染之间的致命协同作用以及数量惊人的耐药结核分枝杆菌菌株威胁着我们控制结核病的能力,即使在发达国家也是如此。为了阻止和扭转这种发展,需要新的治疗方法,大大缩短和简化结核病治疗,并使用新的药物靶点。我们最近发现铜稳态作为结核分枝杆菌的一个重要毒力因子。我们可以证明,结核分枝杆菌铜稳态的遗传扰动诱导铜超敏反应,这是与一个强大的毒力缺陷。铜离子被巨噬细胞用来杀死Mtb,因此与铜依赖性先天免疫功能协同作用的化合物为治疗性干扰创造了新的机会。在这个项目中,我们将开发一个强大的组合高通量筛选(HTS)检测,用于鉴定铜促进药物,要么(i)抑制(ii)的单个组分或增加铜的吸收,从而压倒结核分枝杆菌的内在铜抗性途径。 在目标1中,我们将优化并将用于铜促进药物的HTS筛选测定转移到利用BSL 2批准的Mtb H37Rv突变体的机器人平台。在目标2中,我们将开发和验证新的和更快速的二级检测,这将指导命中优先级。特别是,我们将验证和利用基于流式细胞术的方法来评估药物暴露的无毒Mtb细胞的活力。该评估比传统的CFU计数快1,000倍,与HTS兼容,支持动态读数,每次读取和条件需要不到1,000个单个细胞。设计各种测定以测试所鉴定的命中物是否充当杀菌或抑菌化合物,表现出针对潜伏(非生长)结核分枝杆菌的活性或与抗逆转录病毒药物相互作用。在导致这种应用的研究中,我们已经确定了两个证据, 以铜依赖性方式靶向Mtb并表现出>20的体外治疗指数的概念化合物。在目标3中,我们将进行中试筛选,以评价总体检测性能。在完成该试点活动后,我们打算申请将我们的筛选测定快速通道进入NIH分子库探针生产中心网络(目标4)。

项目成果

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Frank Wolschendorf其他文献

Frank Wolschendorf的其他文献

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{{ truncateString('Frank Wolschendorf', 18)}}的其他基金

HTS for copper-activated inhibitors against MRSA
用于抗 MRSA 的铜激活抑制剂的 HTS
  • 批准号:
    9313203
  • 财政年份:
    2016
  • 资助金额:
    $ 34.07万
  • 项目类别:
HTS for copper-activated inhibitors against MRSA
用于抗 MRSA 的铜激活抑制剂的 HTS
  • 批准号:
    9177088
  • 财政年份:
    2016
  • 资助金额:
    $ 34.07万
  • 项目类别:
HTS for bactericidal inhibitors of M. tuberculosis copper resistance mechanisms
HTS 用于结核分枝杆菌铜耐药机制的杀菌抑制剂
  • 批准号:
    8791597
  • 财政年份:
    2013
  • 资助金额:
    $ 34.07万
  • 项目类别:
HTS for bactericidal inhibitors of M. tuberculosis copper resistance mechanisms
HTS 用于结核分枝杆菌铜耐药机制的杀菌抑制剂
  • 批准号:
    8624657
  • 财政年份:
    2013
  • 资助金额:
    $ 34.07万
  • 项目类别:

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