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.
摘要
我们的长期目标是开发一种新的结核病治疗方法,这是
世界上最具破坏性的疾病,感染了全球约三分之一的人口,并声称更多
每年有150多万人丧生。目前可用的结核病药物的缺点突显了
迫切需要发现新的化合物来有效治疗结核病患者。当前的“空头”
课程“一线疗法包括6-9个月服用多种药物的鸡尾酒。这
旷日持久的治疗源于难以根除结核分枝杆菌的休眠种群
全身各处都有不同的壁龛。出现多药耐药(耐多药结核病)和
极端耐药结核病(XDR-TB)菌株使这种疾病的控制进一步复杂化。
因此,迫切需要具有新作用模式的强效药物。
缩短疗程,体内杀灭耐药、潜伏的结核分枝杆菌。
为了解决这个问题,我们将结合天然产物(NP)的化学多样性和我们的
在类似体内的条件下进行针对结核分枝杆菌的全细胞药物筛选的能力
确定新的支架,为结核病药物开发管道提供燃料。受到我们的发现的鼓舞
在我们的~2500个屏幕上,有许多真菌NP对复制和休眠的结核分枝杆菌具有活性
真菌提取物,在目标1中,我们建议表征活性NP对
识别高优先级样品以进行去卷积和鉴定新型抗结核支架
活动。我们的初步数据支持这样的假设,即在体内筛选NP样本-
在类似的条件下,比如我们的体外休眠模型,我们可以推测出“成功”的化合物
作用于新的目标,这些目标只是基本的,因此在压力下容易受到抑制
在体内遇到的情况。目标2将专注于从
最有效和最有选择性的混合物,确定其化学结构,并传导
抗菌活性和理化性质的综合分析。强大而有力
我们确定的休眠、细胞内和/或耐药结核分枝杆菌的选择性抑制剂
该项目将作为未来开发新候选人的点击到领先的基础
结核病治疗学。
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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