Exploiting Fungal Natural Products to Discover Novel Scaffolds That Inhibit Dormant and Drug-Resistant TB
利用真菌天然产物发现抑制休眠和耐药结核病的新型支架
基本信息
- 批准号:9316820
- 负责人:
- 金额:$ 23.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-01-20 至 2018-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnimal ModelAnti-Bacterial AgentsAnti-Retroviral AgentsAntibioticsAntitubercular AgentsBacillus (bacterium)BacteriaBiological AssayCellsChemical StructureChemicalsClinicalCollectionCommunicable DiseasesCoupledDNA Sequence AlterationDataDevelopmentDiagnosisDiseaseDoseDrug resistanceDrug resistance in tuberculosisExtreme drug resistant tuberculosisFutureGenus MycobacteriumGoalsGranulomaGrowthHIVHeritabilityHypoxiaIn VitroLaboratoriesLeadLibrariesModelingMulti-Drug ResistanceMultidrug-Resistant TuberculosisMycobacterium smegmatisMycobacterium tuberculosisMycophenolateNatural ProductsOklahomaPatientsPenicillinsPharmaceutical PreparationsPhenotypePhysiologicalPopulationPreclinical Drug EvaluationPropertyPublic HealthPyrazinamideRegimenRelapseReportingResolutionResourcesRifampinSamplingSoilSourceStressStructureTestingTherapeuticTreatment FailureTuberculosisUniversitiesantimicrobialbasecytotoxicitydisorder controldrug developmentdrug discoverydrug metabolismefficacy studyfungusimprovedin vivoinhibitor/antagonistkillingsmacrophagenon-compliancenon-tuberculosis mycobacterianovelnovel drug classnovel therapeuticspathogenphase II trialrepositoryresponsescaffoldscreeningstemtherapeutic candidatetreatment durationtuberculosis drugstuberculosis treatment
项目摘要
Summary
Our long-term goal is to develop a novel treatment for Tuberculosis (TB) which is one of the
most devastating diseases worldwide, infecting ~1/3 of the global population and claiming more
than ~1.5 million lives each year. The shortcomings of currently available TB drugs underscore
the urgent need to discover novel compounds to effectively treat TB patients. The current “short
course” front-line regimen involves a cocktail of multiple drugs taken for 6-9 months. This
protracted treatment stems from the difficulty of eradicating dormant populations of Mtb in
various niches throughout the body. The emergence of Multidrug-Resistant (MDR-TB) and
Extremely Drug Resistant (XDR-TB) strains of TB further complicates the control of this disease.
Thus, there is an urgent need for potent drugs with novel modes of action capable of
shortening the course of treatment and killing drug-resistant and dormant Mtb in vivo.
To address this problem we will combine the chemical diversity of natural products (NP) and our
capability to conduct whole-cell drug screening against Mtb under in vivo-like conditions to
identify novel scaffolds to fuel the TB drug development pipeline. Encouraged by our discovery
of numerous fungal NP active against both replicating and dormant Mtb in our screens of ~2500
fungal extracts, in Aim 1 we propose to characterize the potency and selectivity of active NP to
identify high priority samples for deconvolution and identification of novel scaffolds with anti-TB
activity. Our preliminary data support the hypothesis that screening NP samples under in vivo-
like conditions such as our in vitro dormancy model can reveal “hit” compounds presumably
acting on novel targets that are only essential, and thus vulnerable to inhibition, under stress
conditions encountered in vivo. Aim 2 will focus on purifying the active components from the
most potent and selective mixtures, determining their chemical structure, and conducting
comprehensive analysis of antimicrobial activity and physicochemical properties. Potent and
selective inhibitors of dormant, intracellular, and/or drug resistant Mtb that we identify in
this project will serve as the basis for future hit-to-lead development of novel candidate
therapeutics for TB.
总结
我们的长期目标是开发一种新的结核病治疗方法,
世界上最具破坏性的疾病,感染了全球1/3的人口,
每年有超过150万人死亡。目前可用的结核病药物的缺点强调,
迫切需要发现有效治疗结核病患者的新化合物。当前“短
一线疗法包括多种药物的混合疗法,持续6-9个月。这
长期治疗的原因是难以根除结核病的休眠群体,
全身的各种壁龛。耐多药结核病的出现,
极端耐药结核(XDR-TB)菌株使结核病的控制进一步复杂化。
因此,迫切需要具有新的作用模式的强效药物,其能够
缩短疗程,杀灭体内耐药和休眠的结核分枝杆菌。
为了解决这个问题,我们将联合收割机结合天然产品(NP)的化学多样性和我们的
能够在体内样条件下进行抗Mtb的全细胞药物筛选,
确定新型支架,为结核病药物开发管道提供燃料。我们的发现鼓舞了我们
在我们的筛选中,许多真菌NP对复制和休眠的Mtb都有活性,约2500
真菌提取物,在目的1中,我们提出表征活性NP对真菌提取物的效力和选择性。
鉴定用于去卷积和鉴定具有抗TB新型支架的高优先级样品
活动我们的初步数据支持这一假设,即在体内-
类似的条件,如我们的体外休眠模型,可以揭示“命中”化合物,大概
作用于仅是必需的新靶点,因此在压力下易受抑制
体内遇到的条件。目标2将重点关注从植物中纯化活性成分
最有效的和选择性的混合物,确定其化学结构,并进行
抗菌活性和理化性质的综合分析。强效和
选择性抑制剂的休眠,细胞内和/或耐药结核分枝杆菌,我们确定在
该项目将作为未来开发新型候选人的基础
结核病的治疗方法
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)
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Robert Henry Cichewicz其他文献
Robert Henry Cichewicz的其他文献
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{{ truncateString('Robert Henry Cichewicz', 18)}}的其他基金
An LCMS-guided bioanalytical approach for rational natural product library design and optimization
LCMS 引导的生物分析方法,用于合理的天然产物库设计和优化
- 批准号:
10418425 - 财政年份:2022
- 资助金额:
$ 23.53万 - 项目类别:
An LCMS-guided bioanalytical approach for rational natural product library design and optimization
LCMS 引导的生物分析方法,用于合理的天然产物库设计和优化
- 批准号:
10697396 - 财政年份:2022
- 资助金额:
$ 23.53万 - 项目类别:
Fungal natural products targeting antimicrobial resistant Mycoplasma genitalium
针对抗菌药物耐药性生殖支原体的真菌天然产品
- 批准号:
10308114 - 财政年份:2020
- 资助金额:
$ 23.53万 - 项目类别:
Procuring Native Natural Product Producers by In Situ Chimera Assembly
通过原位嵌合体组装采购天然产物生产商
- 批准号:
9065487 - 财政年份:2015
- 资助金额:
$ 23.53万 - 项目类别:
Early Stage Discovery of Natural Products Targeting Anaerobic Protozoal Pathogen
针对厌氧原虫病原体的天然产物的早期发现
- 批准号:
9088344 - 财政年份:2015
- 资助金额:
$ 23.53万 - 项目类别:
Early Stage Discovery of Natural Products Targeting Anaerobic Protozoal Pathogen
针对厌氧原虫病原体的天然产物的早期发现
- 批准号:
9480206 - 财政年份:2015
- 资助金额:
$ 23.53万 - 项目类别:
Sourcing Bioactive Secondary Metabolites from Great Lakes Fungi
从五大湖真菌中采购生物活性次生代谢物
- 批准号:
9054134 - 财政年份:2014
- 资助金额:
$ 23.53万 - 项目类别:
Sourcing Bioactive Secondary Metabolites from Great Lakes Fungi
从五大湖真菌中采购生物活性次生代谢物
- 批准号:
8697723 - 财政年份:2014
- 资助金额:
$ 23.53万 - 项目类别:
New Leads for Triple Negative Breast Cancer from Diverse Natural Sources
来自不同天然来源的三阴性乳腺癌的新线索
- 批准号:
8761726 - 财政年份:2014
- 资助金额:
$ 23.53万 - 项目类别:
Sourcing Bioactive Secondary Metabolites from Great Lakes Fungi
从五大湖真菌中采购生物活性次生代谢物
- 批准号:
9296148 - 财政年份:2014
- 资助金额:
$ 23.53万 - 项目类别:
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