High content, high throughput, diversity screen for novel anti-tubercular agents targeting intracellular bacteria
针对细胞内细菌的新型抗结核药物的高含量、高通量、多样性筛选
基本信息
- 批准号:10526217
- 负责人:
- 金额:$ 29.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-12 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAntibioticsAntitubercular AgentsBacteriaBacterial InfectionsBiologicalBiological AssayCell SurvivalCellsCessation of lifeChemicalsCommunicable DiseasesDataDevelopmentDiversity LibraryDrug resistance in tuberculosisEukaryotic CellEvaluationFutureGenerationsHIVHeterogeneityHost Defense MechanismHumanInfectionLeadLocationMethodsMonitorMycobacterium tuberculosisNew AgentsOutcomePenetrationPersonsPharmaceutical PreparationsPharmacotherapyPhenotypePhysiologicalPopulationPropertyRegimenRunningSeriesTimeTuberculosisWorkantibiotic toleranceaxenic culturebasecounterscreendrug discoverydrug-sensitiveglobal healthinhibitorinterestmacrophagemycobacterialnew therapeutic targetnovelnovel therapeuticspathogenscreeningsmall molecule librariessuccesstargeted agenttuberculosis drugstuberculosis treatment
项目摘要
Summary
Tuberculosis remains a major global health burden with 10 million new cases in 2019 and a latently-infected
population of billions. Deaths from tuberculosis now exceed those from HIV (1.2 million in 2019). Mycobacterium
tuberculosis, the causative agent, is a sophisticated pathogen which can persist for decades in the human host
and which requires lengthy treatment for cure with multiple antibiotics.
One of the features of M. tuberculosis is its ability to survive and replicate inside human cells, including
macrophages, one of the normal host defense mechanisms against infection. Intracellular bacteria are a specific
population which can be hard to kill, in part due to the requirement that molecules enter eukaryotic cells, and in
part due to the different physiological state in which the bacteria persist. Increasing evidence points to a higher
level of antibiotic tolerance in intracellular bacteria, as well as increased heterogeneity.
In order to find new agents, we developed a phenotypic screening method utilizing high content screening to
monitor bacterial and eukaryotic cell survival simultaneously. We ran a pilot screen to identify novel chemical
inhibitors of mycobacterial intracellular replication. We found several series of interest and selected three series
with attractive physicochemical properties. Based on our initial success we propose to expand our effort to run
a larger diverse screening set.
The overall aim of this proposal is to screen a diversity set of molecules against intracellular Mtb and to evaluate
and prioritize hits for future work. We will combine biological activity, profile, mode of action and physicochemical
properties to select series with the most promise. The major outcome of this exploratory proposal will be novel
chemical matter ready to enter the discovery pipeline.
总结
结核病仍然是全球主要的健康负担,2019年新增病例1000万,
数十亿人口。结核病的死亡人数现在超过了艾滋病毒(2019年为120万人)。分枝杆菌
结核病是一种复杂的病原体,可在人体内持续数十年
并且需要使用多种抗生素进行长期治疗。
M.结核病是它在人体细胞内生存和复制的能力,包括
巨噬细胞,正常宿主防御感染的机制之一。细胞内细菌是一种特定的
这可能是很难杀死的,部分原因是分子进入真核细胞的要求,
部分原因是细菌持续存在的不同生理状态。越来越多的证据表明,
细胞内细菌的抗生素耐受性水平以及异质性增加。
为了寻找新的药物,我们开发了一种利用高含量筛选的表型筛选方法,
同时监测细菌和真核细胞的存活。我们做了一个初步筛选来鉴定
分枝杆菌细胞内复制的抑制剂。我们发现了几个感兴趣的系列,并选择了三个系列
具有吸引人的物理化学性质。基于我们最初的成功,我们建议扩大我们的努力,
一个更大的多样化筛选集。
该提案的总体目标是筛选针对细胞内Mtb的分子的多样性集,并评估其对细胞内Mtb的抑制作用。
并为未来的工作划分优先级。我们将结合联合收割机的生物活性,概况,作用模式和物理化学
属性来选择最有希望的系列。这一探索性建议的主要成果将是新颖的
化学物质准备进入发现管道。
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 }}
Tanya Parish其他文献
Tanya Parish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('Tanya Parish', 18)}}的其他基金
Developing triazolopyrimidines as novel anti-tubercular agents
开发三唑并嘧啶作为新型抗结核药物
- 批准号:
10672660 - 财政年份:2022
- 资助金额:
$ 29.54万 - 项目类别:
High content, high throughput, diversity screen for novel anti-tubercular agents targeting intracellular bacteria
针对细胞内细菌的新型抗结核药物的高含量、高通量、多样性筛选
- 批准号:
10621242 - 财政年份:2022
- 资助金额:
$ 29.54万 - 项目类别:
The role of Esx-3 in mediating drug resistance
Esx-3在介导耐药性中的作用
- 批准号:
10457807 - 财政年份:2020
- 资助金额:
$ 29.54万 - 项目类别:
The role of Esx-3 in mediating drug resistance
Esx-3在介导耐药性中的作用
- 批准号:
9984947 - 财政年份:2020
- 资助金额:
$ 29.54万 - 项目类别:
High Content Screening of Mycobacterium Tuberculosis
结核分枝杆菌的高内涵筛选
- 批准号:
10084646 - 财政年份:2020
- 资助金额:
$ 29.54万 - 项目类别:
The role of Esx-3 in mediating drug resistance
Esx-3在介导耐药性中的作用
- 批准号:
10084640 - 财政年份:2020
- 资助金额:
$ 29.54万 - 项目类别:
High throughput assays to detect inhibition of a key M. tuberculosis protease
高通量测定检测关键结核分枝杆菌蛋白酶的抑制
- 批准号:
8438134 - 财政年份:2013
- 资助金额:
$ 29.54万 - 项目类别:
High throughput assays to detect inhibition of a key M. tuberculosis protease
高通量测定检测关键结核分枝杆菌蛋白酶的抑制
- 批准号:
8702075 - 财政年份:2013
- 资助金额:
$ 29.54万 - 项目类别:
相似海外基金
Can antibiotics disrupt biogeochemical nitrogen cycling in the coastal ocean?
抗生素会破坏沿海海洋的生物地球化学氮循环吗?
- 批准号:
2902098 - 财政年份:2024
- 资助金额:
$ 29.54万 - 项目类别:
Studentship
The role of RNA repair in bacterial responses to translation-inhibiting antibiotics
RNA修复在细菌对翻译抑制抗生素的反应中的作用
- 批准号:
BB/Y004035/1 - 财政年份:2024
- 资助金额:
$ 29.54万 - 项目类别:
Research Grant
Metallo-Peptides: Arming Cyclic Peptide Antibiotics with New Weapons to Combat Antimicrobial Resistance
金属肽:用新武器武装环肽抗生素以对抗抗菌素耐药性
- 批准号:
EP/Z533026/1 - 财政年份:2024
- 资助金额:
$ 29.54万 - 项目类别:
Research Grant
DYNBIOTICS - Understanding the dynamics of antibiotics transport in individual bacteria
DYNBIOTICS - 了解抗生素在单个细菌中转运的动态
- 批准号:
EP/Y023528/1 - 财政年份:2024
- 资助金额:
$ 29.54万 - 项目类别:
Research Grant
Towards the sustainable discovery and development of new antibiotics
迈向新抗生素的可持续发现和开发
- 批准号:
FT230100468 - 财政年份:2024
- 资助金额:
$ 29.54万 - 项目类别:
ARC Future Fellowships
Engineering Streptomyces bacteria for the sustainable manufacture of antibiotics
工程化链霉菌用于抗生素的可持续生产
- 批准号:
BB/Y007611/1 - 财政年份:2024
- 资助金额:
$ 29.54万 - 项目类别:
Research Grant
The disulfide bond as a chemical tool in cyclic peptide antibiotics: engineering disulfide polymyxins and murepavadin
二硫键作为环肽抗生素的化学工具:工程化二硫多粘菌素和 murepavadin
- 批准号:
MR/Y033809/1 - 财政年份:2024
- 资助金额:
$ 29.54万 - 项目类别:
Research Grant
Role of phenotypic heterogeneity in mycobacterial persistence to antibiotics: Prospects for more effective treatment regimens
表型异质性在分枝杆菌对抗生素持久性中的作用:更有效治疗方案的前景
- 批准号:
494853 - 财政年份:2023
- 资助金额:
$ 29.54万 - 项目类别:
Operating Grants
Imbalance between cell biomass production and envelope biosynthesis underpins the bactericidal activity of cell wall -targeting antibiotics
细胞生物量产生和包膜生物合成之间的不平衡是细胞壁靶向抗生素杀菌活性的基础
- 批准号:
2884862 - 财政年份:2023
- 资助金额:
$ 29.54万 - 项目类别:
Studentship
Narrow spectrum antibiotics for the prevention and treatment of soft-rot plant disease
防治植物软腐病的窄谱抗生素
- 批准号:
2904356 - 财政年份:2023
- 资助金额:
$ 29.54万 - 项目类别:
Studentship