Insertional Mutagenesis of Candida auris using Agrobacterium tumefaciens
使用根癌农杆菌插入诱变耳念珠菌
基本信息
- 批准号:9808697
- 负责人:
- 金额:$ 23.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-01 至 2021-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAmmoniumAntibiotic susceptibilityAntibioticsAntifungal AgentsAzolesCandidaCandidate Disease GeneCell SurvivalCellsCenters for Disease Control and Prevention (U.S.)CharacteristicsClinicClinicalCommunicable DiseasesCountryDataDevelopmentDisinfectionDrug TargetingDrug resistanceEssential GenesExposure toFormulationFrequenciesFungi ModelFurnitureFutureGenerationsGenesGenomeGenomic DNAGenomicsGoalsHumanInfectionInsertional MutagenesisLeadLibrariesMammalian CellMapsMattressesMedicalMethodsModelingModificationMorbidity - disease rateMulti-Drug ResistanceMycosesNatural ProductsNatural ResistanceNatureOrganismPatientsPharmaceutical PreparationsPoisonProbabilityPublic HealthRefractoryReportingResearchResistanceResistance developmentRhizobium radiobacterRiskSaccharomyces cerevisiaeSiteSodium ChlorideSpeedStructureSystemTestingUntranslated RNAbasecell transformationdeep sequencingdensitydrug candidatedrug discoveryexhaustfungusimprovedknockout genemortalitynext generationnext generation sequencingnovel sequencing technologynovel strategiespathogenic bacteriapathogenic fungusrapid techniqueresponsescreeningsmall molecule librariestransmission processtreatment choice
项目摘要
Drug resistance is arguably one of the most pressing problems in infectious disease. Resistance can occur
naturally, where organisms exhbit natural low-level antibiotic susceptibility or it can occur spontaneously after
exposure to antibiotics. Fungi pose special problems to antibiotic development because there are very limited
antibiotic choices for treatment. Many promising lead compounds that are toxic to fungi unfortunately are
toxic to mamals due to the similar eukaryoctic cellular organization. Consequently antifungal development
has always been difficult for fungi. Candida auris is an emerging fungal pathogen that displays a high
frequency of natural resistance to first line antifungal treatment, but also has been shown to develop
resistance to all know antifugals. The extremely rapid spread of this fungus around the world and high
mortality rate (~30-80% depending on country) has amplified known problems in treating systemic mycosis:
the lack of antifungal choices for fungal infections. Most of what we know about antifungal drug research is
derived from studies of non-pathogenic model fungi, such as Saccharomyces cerevisiae, which are
unsuitable as pan-fungal models. To address this issue, we will develop a method that rapidly interrogates
the C. auris genome to reveal genes that are potential antifungal targets by virtue of their function being
essential to cell survival. The major objective of this study will be to develop a way to rapidly and
inexpensively identify these targets. To accomplish this goal we will develop an insertional mutagenesis
system based on the bacterial pathogen, Agrobacterium tumefaciens for C. auris. The first aim will be to
improve the existing Agrobacterium tumefaciens transformation efficiency to yield enough transformants to
produce a saturated insertional mutagenesis map. We will next develop a capture-probe based enrichment
method for recovering insertion site fragments from the predominating non-junctional genomic DNA
background. Finally, we will apply deep sequencing to these enriched fragments to identify each insertion site
and its neighboring flanking genomic DNA, and ultimately assemble a high density insertion map that will be
used to identify genes that are essential for survival, and therefore, potential antifungal targets.
耐药性可以说是传染病中最紧迫的问题之一。可能会出现耐药性
自然地,生物体表现出天然的低水平抗生素敏感性,或者可以在
接触抗生素。真菌对抗生素的开发造成了特殊的问题,因为真菌的数量非常有限
治疗时选择抗生素。不幸的是,许多有前景的先导化合物对真菌有毒。
由于与真核细胞组织相似,对哺乳动物有毒。因此抗真菌的发展
对于真菌来说一直是困难的。耳念珠菌是一种新兴的真菌病原体,具有很高的致病性
对一线抗真菌治疗产生自然耐药性的频率,但也已被证明会发展
对所有已知的抗真菌药物都有抵抗力。这种真菌在世界范围内极其迅速地传播
死亡率(~30-80%,具体取决于国家)加剧了治疗系统性真菌病的已知问题:
缺乏针对真菌感染的抗真菌选择。我们对抗真菌药物研究的了解大部分是
源自对非致病性模型真菌的研究,例如酿酒酵母,
不适合作为泛真菌模型。为了解决这个问题,我们将开发一种快速询问的方法
耳念珠菌基因组揭示了由于其功能而成为潜在抗真菌靶标的基因
对细胞生存至关重要。本研究的主要目标是开发一种快速且有效的方法
廉价地识别这些目标。为了实现这一目标,我们将开发插入诱变
基于细菌病原体根癌农杆菌的系统。第一个目标是
提高现有根癌农杆菌转化效率,产生足够的转化体
产生饱和插入诱变图。接下来我们将开发一种基于捕获探针的富集
从主要非连接基因组 DNA 中回收插入位点片段的方法
背景。最后,我们将对这些富集片段进行深度测序,以识别每个插入位点
及其邻近的侧翼基因组 DNA,并最终组装出高密度插入图谱,该图谱将被
用于识别生存所必需的基因,因此也是潜在的抗真菌靶标。
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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BRIAN WICKES其他文献
BRIAN WICKES的其他文献
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{{ truncateString('BRIAN WICKES', 18)}}的其他基金
Development of a rapid, pan fungal diagnostic assay
快速、泛真菌诊断测定的开发
- 批准号:
10552690 - 财政年份:2021
- 资助金额:
$ 23.06万 - 项目类别:
Development of a rapid, pan fungal diagnostic assay
快速、泛真菌诊断测定的开发
- 批准号:
10211503 - 财政年份:2021
- 资助金额:
$ 23.06万 - 项目类别:
Development of a rapid, pan fungal diagnostic assay
快速、泛真菌诊断测定的开发
- 批准号:
10335282 - 财政年份:2021
- 资助金额:
$ 23.06万 - 项目类别:
Pan-Fungal Essential Gene Discovery for Antifungal Targeting
抗真菌靶向的泛真菌必需基因发现
- 批准号:
9056983 - 财政年份:2015
- 资助金额:
$ 23.06万 - 项目类别:
Pan-Fungal Essential Gene Discovery for Antifungal Targeting
抗真菌靶向的泛真菌必需基因发现
- 批准号:
8970250 - 财政年份:2015
- 资助金额:
$ 23.06万 - 项目类别:
Congenic strains of serotype A Cryptococcus neoformans
A血清型新型隐球菌的同源菌株
- 批准号:
6603508 - 财政年份:2003
- 资助金额:
$ 23.06万 - 项目类别:
Congenic strains of serotype A Cryptococcus neoformans
A血清型新型隐球菌的同源菌株
- 批准号:
6843089 - 财政年份:2003
- 资助金额:
$ 23.06万 - 项目类别:
Congenic strains of serotype A Cryptococcus neoformans
A血清型新型隐球菌的同源菌株
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6699639 - 财政年份:2003
- 资助金额:
$ 23.06万 - 项目类别:
MATING TYPE AND VIRULENCE IN CRYPTOCOCCUS NEOFORMANS
新型隐球菌的交配类型和毒力
- 批准号:
6373899 - 财政年份:1998
- 资助金额:
$ 23.06万 - 项目类别:
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