Characterization and membrane-biogenesis of Streptococcus mutans magnesium transporters
变形链球菌镁转运蛋白的表征和膜生物发生
基本信息
- 批准号:10544751
- 负责人:
- 金额:$ 15.25万
- 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:2022-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAlloysAnti-Bacterial AgentsAntibioticsBacteriaBacterial ProteinsBinding ProteinsBiochemicalBioinformaticsBiological ProcessCationsCellsChargeCommunicable DiseasesCompetenceDataDentalDental EnamelDental ImplantsDental cariesDependenceDevelopmentDivalent CationsEndocarditisEnvironmentEnzymesEscape MutantEvaluationExposure toFoundationsFutureGenesGeneticGenetic ScreeningGenetic TranscriptionGoalsGrowthHealth Care CostsHomeostasisHomologous GeneHumanHuman bodyImplantInfective endocarditisIonsMagnesiumMeasurementMembraneMembrane ProteinsMetalsMicrobial BiofilmsMolecular CloningMutagenesisMycobacterium tuberculosisNucleic AcidsOral cavityPathway interactionsPersonsPhenotypePlayPredispositionProtein translocationProteinsProteomicsQuality of lifeRegulationResistanceResistance developmentRibosomesRoleSalivaSaltsSignal Recognition ParticleStreptococcus mutansSuppressor MutationsSurgeonTherapeuticTooth structureToothpasteToxic effectTransition ElementsVertebratesVirulenceWorkanticariesbonecofactorcombinatorialdental agentdivalent metalefflux pumpexperienceforward geneticsgain of functiongenetic approachmembrane biogenesismutantnoveloral bacteriaoral pathogenoral streptococcipathogenprotein transportreverse geneticsskillstooluptake
项目摘要
Project Summary
Dental caries is a ubiquitous infectious disease that impacts the quality of life of billions of people
worldwide. According to the Surgeon General (2020), ~USD 125 billion dollars are spent annually on
related treatments in the USA alone. A major causative agent of dental caries is Streptococcus mutans,
which is also associated with infectious endocarditis. The native environment of S. mutans is rich in
metal cations including Ca2+, K+, and Mg2+. In fact, Mg2+ is the most abundant divalent metal cation in
bacteria and fourth most abundant in vertebrates including humans. Of the total Mg2+ content in the
human body, 60‐70% is found in bones and teeth. Therefore, the oral bacterium, S. mutans, is
constantly exposed to Mg2+ salts. Magnesium is an important component of toothpastes and dental
implants. Despite its abundance and its requirement to support bacterial growth and virulence , Mg2+
homeostasis has not yet been studied in S. mutans, or other oral streptococci. A few isolated studies
discussed the significance of supplemental Mg2+ salts for S. mutans biofilm formation and genetic
competence, but Mg2 transport is not understood. We will address Mg2+ homeostasis from a novel
perspective, where we will not only characterize the transporters, but also study their insertion into
the membrane. Membrane localization/insertion is a key requisite for the proper functioning of all
membrane proteins. Deletion of putative transporters singly and in combination, followed by
measurement of cellular metal content will establish identity of Mg2+ transporters. Compensatory
uptake/efflux by other divalent metal cation transporters have been recognized to interfere with Mg2+
homeostasis in other bacteria. Therefore, Mn2+ and Fe2+ transporters are also included in this study.
Mutants defective in putative Mg2+ transporter(s) will be evaluated at the level of transcription,
cellular metal content, and insertion into membrane. Next, we will use a forward genetic screen to
identify gain of function/suppressor mutations in Mg2+‐replete/deplete conditions using mutants
defective in Mg2+ transporters, or in mutants lacking membrane biogenesis machinery components
that impact Mg2+ homeostasis. We appreciate the significance of proper localization of transporters to
their activity; therefore, we will apply the experience/tools/skills of our lab to study that aspect of
magnesium homeostasis in S. mutans. Characterization of insertion pathways will involve
construction and characterization of combinatorial mutants of membrane biogenesis components
with Mg2+ transporters, and phenotypic analysis following that used for characterization of the
transport mutants. Molecular cloning, reverse and forward genetics, bioinformatics, and biochemical
approaches will be utilized to address the aims of this proposal. Ultimately a better understanding of
Mg2+ homeostasis in S. mutans is expected to guide future development of novel anti‐caries strategies.
项目摘要
龋齿是一种普遍存在的传染病,影响数十亿人的生活质量
国际吧根据卫生局局长(2020年)的数据,每年约有1250亿美元用于
仅在美国就有相关治疗。龋齿的主要病原体是变形链球菌,
这也与感染性心内膜炎有关。S.变种人富含
金属阳离子,包括Ca 2+、K+和Mg 2+。事实上,Mg 2+是在水溶液中最丰富的二价金属阳离子。
细菌和第四最丰富的脊椎动物包括人类。镁离子的总含量
在人体中,60 - 70%存在于骨骼和牙齿中。因此,口腔细菌S.穆坦斯群岛
不断暴露于Mg 2+盐中。镁是牙膏和牙科的重要成分
植入物.尽管Mg 2+的丰度和支持细菌生长和毒力的要求,
在S.变形链球菌或其它口腔链球菌。一些孤立的研究
讨论了添加Mg ~(2+)盐对S.变形菌生物膜形成和遗传
能力,但镁运输是不了解。我们将从一种新颖的
的观点,在那里我们不仅将表征转运蛋白,而且还研究它们插入到
膜。膜定位/插入是所有细胞正常运作的关键条件。
膜蛋白单独和联合缺失推定转运蛋白,然后
细胞金属含量的测量将确定Mg 2+转运蛋白的身份。补偿性
已认识到其他二价金属阳离子转运蛋白的摄取/流出会干扰Mg 2 +
其他细菌的体内平衡。因此,Mn 2+和Fe 2+转运蛋白也包括在本研究中。
将在转录水平评价推定的Mg 2+转运蛋白缺陷突变体,
细胞金属含量和插入膜中。接下来,我们将使用正向遗传筛选,
使用突变体鉴定Mg 2 +-充满/耗尽条件下功能/抑制突变的获得
Mg 2+转运蛋白缺陷,或缺乏膜生物发生机制组件的突变体
影响Mg 2+体内平衡。我们明白适当地将运输商本地化,
因此,我们将运用我们实验室的经验/工具/技能来研究他们的活动,
镁稳态在S.变异体插入途径的表征将涉及
膜生物发生组分组合突变体的构建和表征
与Mg 2+转运蛋白,和表型分析后,用于表征的
运输突变体分子克隆、反向和正向遗传学、生物信息学和生物化学
将采用各种办法来实现本提案的目标。最终,更好地理解
Mg ~(2+)稳态在S.预计mutans将指导新的抗龋齿策略的未来发展。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Surabhi Mishra其他文献
Surabhi Mishra的其他文献
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{{ truncateString('Surabhi Mishra', 18)}}的其他基金
Characterization and membrane-biogenesis of Streptococcus mutans magnesium transporters
变形链球菌镁转运蛋白的表征和膜生物发生
- 批准号:
10353066 - 财政年份:2022
- 资助金额:
$ 15.25万 - 项目类别:
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