A Novel High-Throughput Exploration of DNA Supercoiling toward the Therapeutic Manipulation of Bacteria
DNA 超螺旋的新型高通量探索对细菌的治疗性操作
基本信息
- 批准号:10741397
- 负责人:
- 金额:$ 25.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-17 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAdenosine DiphosphateAdenosine TriphosphateAnimal ModelAnti-Bacterial AgentsAnti-Infective AgentsAntibioticsAntimicrobial ResistanceBacteriaBacterial DNABacterial PhysiologyBehaviorBiologicalCellsChloroquineDNADNA GyraseDevelopmentEnzymesEvaluationExposure toFaceFluorescenceFluoroquinolonesGenesGeneticGrowthHumanInfectionInfectious AgentLaboratoriesLinkMagnesiumMethodsModelingMutateMutationMycobacterium tuberculosisOsmolar ConcentrationOutputPathway interactionsPharmaceutical PreparationsPhenotypePhysiologicalPolyaminesPredispositionProcessPropertyProteinsPutrescineRNARelaxationReportingResearchSalmonella typhimuriumSepharoseSiteSpermidineStressSuperhelical DNATechnologyTemperatureTherapeuticTimeToxic effectType I DNA Topoisomerasesantimicrobialbacterial resistancebaseenzyme activityexperienceexposure pathwaygene discoveryhigh throughput screeninghuman pathogeninhibitormutantnovelnovel strategiespathogenplasmid DNAprogramsresponsetargeted agenttechnological innovation
项目摘要
PROJECT SUMMARY
Bacterial survival requires a nearly constant and specific global DNA supercoiling status.
This is achieved by the opposing functions of the DNA-relaxing topoisomerase I and
DNA-compacting DNA gyrase. We propose the first unbiased high-throughput
exploration of genes governing the abundance and activity of these enzymes, which
hold great untapped promise for therapeutic manipulation. How pathogens change
DNA supercoiling during infection conceals vulnerabilities critical to overcoming the
toxic effects of current DNA gyrase inhibitors and emergence of bacteria resistant to
these agents. We will examine mutants of the pathogen Salmonella enterica serovar
Typhimurium for altered DNA supercoiling in infection-relevant conditions by deploying
Fluorescence Evaluation of DNA Supercoiling – or FEDS – a new high-throughput
method developed in our laboratory that reports the global DNA supercoiling status of
living bacteria. To expose the genetic basis for altered DNA supercoiling, we will identify
the mutated genes and explore genetic interactions among the mutations to reveal
novel instances of synthetic lethality, thereby uncovering both novel genetic pathways
and novel ways to manipulate DNA supercoiling. We will solve the bases for the DNA
supercoiling behavior of the identified mutants by determining the amounts of DNA
gyrase and topoisomerase I as well as the abundance of adenosine triphosphate,
adenosine diphosphate, and specific polyamines – all critical regulators of DNA gyrase
activity. The proposed research program pioneers the physiological understanding of an
essential cellular property exploitable in a wide range of bacterial species to identify
novel targets for antibacterial agents.
项目总结
细菌的生存需要一个几乎恒定和特定的全球DNA超螺旋状态。
这是通过DNA松弛拓扑异构酶I和拓扑异构酶I的相反功能实现的
DNA压缩DNA旋转酶。我们提出了第一个无偏高吞吐量
探索控制这些酶的丰度和活性的基因,这是
拥有巨大的未开发的治疗操作的前景。病原体是如何变化的
感染过程中的DNA超级卷曲隐藏了对克服
当前DNA旋转酶抑制剂的毒性效应和耐药细菌的出现
这些特工。我们将检测病原体肠炎沙门氏菌血清型的突变
小鼠在感染相关条件下通过部署用于改变的DNA超螺旋
一种新的高通量DNA超螺旋或FEDS的荧光评价
我们实验室开发的报告全球DNA超螺旋状态的方法
活细菌。为了揭示改变的DNA超螺旋的遗传基础,我们将识别
并探索突变基因之间的遗传交互作用,揭示突变
合成致命性的新实例,从而揭示了两种新的遗传途径
以及操纵DNA超级卷曲的新方法。我们将解开DNA的碱基
通过测定DNA含量确定突变体的超螺旋行为
旋转酶和拓扑异构酶I以及三磷酸腺苷的丰度,
二磷酸腺苷和特定的多胺--DNA旋转酶的关键调节因子
活动。拟议的研究计划开创了对心脏的生理学理解。
在广泛的细菌物种中可利用的基本细胞特性来识别
抗菌药物的新靶点。
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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Eduardo Groisman其他文献
Eduardo Groisman的其他文献
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{{ truncateString('Eduardo Groisman', 18)}}的其他基金
Elucidating the Sensing Abilities of Virulence Regulatory Systems
阐明毒力调节系统的感知能力
- 批准号:
10452800 - 财政年份:2021
- 资助金额:
$ 25.13万 - 项目类别:
Control of gut colonization by the prominent gut bacterium Bacteroides thetaiotaomicron
著名肠道细菌多形拟杆菌对肠道定植的控制
- 批准号:
10444020 - 财政年份:2018
- 资助金额:
$ 25.13万 - 项目类别:
Control of carbohydrate utilization in the prominent gut bacterium Bacteroides thetaiotaomicron
控制主要肠道细菌多形拟杆菌中碳水化合物的利用
- 批准号:
9757784 - 财政年份:2018
- 资助金额:
$ 25.13万 - 项目类别:
Control of carbohydrate utilization in the prominent gut bacterium Bacteroides thetaiotaomicron
控制主要肠道细菌多形拟杆菌中碳水化合物的利用
- 批准号:
9921411 - 财政年份:2018
- 资助金额:
$ 25.13万 - 项目类别:
Control of gut colonization by the prominent gut bacterium Bacteroides thetaiotaomicron
著名肠道细菌多形拟杆菌对肠道定植的控制
- 批准号:
10646419 - 财政年份:2018
- 资助金额:
$ 25.13万 - 项目类别:
2016 Microbial Stress Response GRC & GRS:Sensing, Adaptation and Evolution in Microbes that Experience Stress
2016微生物应激反应GRC
- 批准号:
9198080 - 财政年份:2016
- 资助金额:
$ 25.13万 - 项目类别:
MOLECULAR AND STRUCTURAL BASES OF POLYMYXIN RESISTANCE
多粘菌素抗性的分子和结构基础
- 批准号:
2451725 - 财政年份:1998
- 资助金额:
$ 25.13万 - 项目类别:
MOLECULAR AND STRUCTURAL BASES OF POLYMYXIN RESISTANCE
多粘菌素抗性的分子和结构基础
- 批准号:
6349841 - 财政年份:1998
- 资助金额:
$ 25.13万 - 项目类别:
MOLECULAR AND STRUCTURAL BASES OF POLYMYXIN RESISTANCE
多粘菌素抗性的分子和结构基础
- 批准号:
6497089 - 财政年份:1998
- 资助金额:
$ 25.13万 - 项目类别:
Molecular and Structural Bases of Polymyxin Resistance
多粘菌素耐药性的分子和结构基础
- 批准号:
6909390 - 财政年份:1998
- 资助金额:
$ 25.13万 - 项目类别:
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