Bacterial Second Messenger Mediated Virulence Regulation in Streptococcus mutans
细菌第二信使介导的变形链球菌毒力调节
基本信息
- 批准号:10227894
- 负责人:
- 金额:$ 31.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-03 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdenosine MonophosphateAdenylate CyclaseAnimal ModelAntibiotic ResistanceBacteriaBacterial InfectionsBasic ScienceBindingBiochemicalBiological AssayCell physiologyChronicCodeCommunicable DiseasesComplexCrystallizationDental ModelsDental cariesDevelopmentDietary SugarsDiseaseEnzymesEtiologyExhibitsFutureGene SilencingGenesGeneticGlucansGlucosyltransferasesGrowthIn VitroIncidenceInfectious AgentLactic acidLeadLinkMediatingMicrobial BiofilmsMicrobiologyModelingMolecularNatureOral cavityOxidative StressPathogenesisPathway interactionsPeriodicityPharmaceutical ChemistryPhenotypePlayProductionPropertyPublic HealthPublishingRattusRegulationResearch PersonnelResistance to infectionRoleSchemeSecond Messenger SystemsSignal PathwaySignal TransductionSignaling MoleculeStaphylococcus aureusStreptococcusStreptococcus mutansStreptococcus pneumoniaeStressStructureStructure-Activity RelationshipTestingTherapeuticTooth DemineralizationVirulenceVirulence FactorsVirulentbasebiological adaptation to stresscombatdental agentdental biofilmdesigndrug discoveryeffective therapyfitnessin vivoinsightmicrobialnovelnovel strategiesoral bacteriaoral streptococcipathogenphosphoric diester hydrolasepreventreceptorreceptor bindingresponsesmall moleculestructural biologytherapeutic targettooth surfacetrait
项目摘要
ABSTRACT
Recently a new bacterial second messenger termed cyclic di-adenosine monophosphate(c-di-AMP) has been
identified and shown to play vital roles in diverse bacterial cellular processes. C-di-AMP is essential in many
Gram-positive pathogens including Staphylococcus aureus and Streptococcus pneumoniae. We and others
have found that c-di-AMP is not essential in Streptococcus mutans, an important etiological agent of dental caries
(cavity), but regulates cariogenic biofilm formation, bacterial stress responses, and dynamic polymicrobial
interactions that are crucial for S. mutans fitness and virulence. Little is known about the role of c-di-AMP
signaling pathways that modulate distinct and conserved virulent properties found in S. mutans and other
pathogens. In this proposal, we use S. mutans as a model to elucidate virulence regulation mediated by this
emerging signaling molecule. Inactivation of the gene coding for c-di-AMP producing enzyme reduced bacterial
colonization and virulence in a rat model of dental caries, demonstrating a critical role of c-di-AMP in S. mutans
virulence. Moreover, c-di-AMP-mediated virulence networks are integrated into a key response regulator VicR-
modulated signaling through a newly identified c-di-AMP binding receptor (CabPA). These novel findings led us
to hypothesize that c-di-AMP regulates biofilm formation and other virulence properties via multiple new
pathways, which represent major potential therapeutic targets to develop novel and selective anti-virulence
compounds. Two specific aims are proposed to test the hypothesis: 1) To elucidate c-di-AMP and its receptor
CabPA mediated signaling pathways that modulate the biofilm formation and other virulence properties; 2) To
develop new small molecule compounds that modulate S. mutans virulence by targeting the c-di-AMP producing
enzyme. The proposal would allow us to identify new signaling components and unknown dynamic interactions
in c-di-AMP-mediated pathways responsible for the biofilm formation, oxidative stress, and bacterial
competitiveness, and uncover potential therapeutic targets, which would facilitate the future development of new
small molecule compounds that are amenable for drug discovery. The proposal tests a new hypothesis that links
c-di-AMP signaling to VicR-mediated expression of a variety of virulence genes through a distinct c-di-AMP
receptor, and documents non-essential nature of c-di-AMP signaling in S. mutans, and explores the translational
potential using anti-virulence strategy. Successful completion of this application will have a direct impact on
public health as dental caries and other infectious conditions are widespread due to antibiotic resistance and
lack of effective treatment options. Development of anti-S. mutans virulence strategy in the proposal is also
relevant to devise species-specific anti-virulence strategy targeting significant pathogens such as S. aureus and
S. pneumoniae, which should open a new venue to the design of new anti-infectious agents to combat microbial
infection and antibiotic resistance.
摘要
最近,一种新的细菌第二信使环二腺苷一磷酸(c-di-amp)被发现
被发现并被证明在不同的细菌细胞过程中发挥重要作用。C-di-AMP在许多情况下是必不可少的
革兰氏阳性病原体包括金黄色葡萄球菌和肺炎链球菌。我们和其他人
已经发现c-di-AMP在变形链球菌中不是必需的,变形链球菌是龋齿的重要病原体
(空洞),但调节致龋性生物膜的形成、细菌应激反应和动态多聚菌素
对变形链球菌的适合性和毒力至关重要的相互作用。人们对c-di-amp的作用知之甚少
在变形链球菌和其他细菌中发现的调节不同和保守的毒力特性的信号通路
病原体。在这项建议中,我们使用变形链球菌作为模型来阐明由该基因介导的毒力调节。
新兴的信号分子。C-二-AMP产生酶编码基因失活还原细菌
C-diAMP在变形链球菌中的关键作用在龋齿大鼠模型中的定植和毒力
致命性。此外,c-di-amp介导的毒力网络被整合到一个关键的反应调节因子Vicr-2中。
通过新发现的c-di-AMP结合受体(CabPA)调节信号。这些新奇的发现使我们
假设c-diAMP通过多个新的新基因调控生物膜的形成和其他毒力特性
代表开发新的和选择性抗毒力的主要潜在治疗靶点的途径
化合物。提出了两个特定的目的来检验这一假说:1)阐明c-diamp及其受体。
CabPA介导的信号通路,调节生物膜的形成和其他毒力特性;2)
通过靶向c-diAMP的产生来开发新的小分子化合物来调节变形链球菌的毒力
酵素。该提案将使我们能够识别新的信令组件和未知的动态交互
在c-di-AMP介导的生物被膜形成、氧化应激和细菌途径中
竞争力,并发现潜在的治疗靶点,这将促进新的
可用于药物发现的小分子化合物。该提案测试了一种新的假设,即
C-di-AMP通过不同的c-di-AMP信号转导VICR介导的多种毒力基因的表达
受体,并记录了c-di-AMP信号在变形链球菌中的非本质性质,并探索了
有潜力使用抗毒力策略。成功完成这项申请将直接影响到
由于抗生素耐药性和其他感染性疾病,龋齿和其他传染病等公共卫生问题普遍存在
缺乏有效的治疗选择。抗S抗体的研究进展变种人的毒力策略也在提案中
与针对金黄色葡萄球菌和金黄色葡萄球菌等重要病原体制定针对特定物种的抗毒力战略有关
肺炎链球菌,这应该为设计新的抗感染剂来对抗微生物开辟了一个新的场所
感染和抗生素耐药性。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Hui Wu其他文献
Hui Wu的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Hui Wu', 18)}}的其他基金
PORT (Portland Oral health Research Training)
PORT(波特兰口腔健康研究培训)
- 批准号:
10651720 - 财政年份:2021
- 资助金额:
$ 31.47万 - 项目类别:
PORT (Portland Oral health Research Training)
PORT(波特兰口腔健康研究培训)
- 批准号:
10651805 - 财政年份:2021
- 资助金额:
$ 31.47万 - 项目类别:
PORT (Portland Oral health Research Training)
PORT(波特兰口腔健康研究培训)
- 批准号:
10270572 - 财政年份:2021
- 资助金额:
$ 31.47万 - 项目类别:
PORT (Portland Oral health Research Training)
PORT(波特兰口腔健康研究培训)
- 批准号:
10437867 - 财政年份:2021
- 资助金额:
$ 31.47万 - 项目类别:
PORT (Portland Oral health Research Training)
PORT(波特兰口腔健康研究培训)
- 批准号:
10414195 - 财政年份:2021
- 资助金额:
$ 31.47万 - 项目类别:
PORT (Portland Oral health Research Training)
PORT(波特兰口腔健康研究培训)
- 批准号:
10437949 - 财政年份:2021
- 资助金额:
$ 31.47万 - 项目类别:
Glycosylation and Biogenesis of Streptococcal Adhesins
链球菌粘附素的糖基化和生物合成
- 批准号:
10300579 - 财政年份:2020
- 资助金额:
$ 31.47万 - 项目类别:
Glycosylation and Biogenesis of Streptococcal Adhesins
链球菌粘附素的糖基化和生物合成
- 批准号:
10227893 - 财政年份:2020
- 资助金额:
$ 31.47万 - 项目类别:
Bacterial Second Messenger Mediated Virulence Regulation in Streptococcus mutans
细菌第二信使介导的变形链球菌毒力调节
- 批准号:
10545763 - 财政年份:2020
- 资助金额:
$ 31.47万 - 项目类别:
相似海外基金
Late-Stage Functionalisation of Cyclic Guanosine Monophosphate - Adenosine Monophosphate
环单磷酸鸟苷-单磷酸腺苷的后期功能化
- 批准号:
2751533 - 财政年份:2022
- 资助金额:
$ 31.47万 - 项目类别:
Studentship
The Role of Chronic Pharmacological Adenosine Monophosphate-Activated Protein Kinase Activation at the Neuromuscular Junction
慢性药理学单磷酸腺苷激活蛋白激酶激活在神经肌肉接头处的作用
- 批准号:
575833-2022 - 财政年份:2022
- 资助金额:
$ 31.47万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Master's
Targeting adenosine monophosphate activated protein kinase (AMPK) to reduce cocaine relapse
靶向单磷酸腺苷激活蛋白激酶 (AMPK) 减少可卡因复吸
- 批准号:
10593045 - 财政年份:2022
- 资助金额:
$ 31.47万 - 项目类别:
Targeting adenosine monophosphate activated protein kinase (AMPK) to reduce cocaine relapse
靶向单磷酸腺苷激活蛋白激酶 (AMPK) 减少可卡因复吸
- 批准号:
10303255 - 财政年份:2022
- 资助金额:
$ 31.47万 - 项目类别:
The regulation of electrical coupling between neuroendocrine cells by cyclic adenosine monophosphate and protein kinase A
环磷酸腺苷与蛋白激酶A对神经内分泌细胞电耦合的调节
- 批准号:
565217-2021 - 财政年份:2021
- 资助金额:
$ 31.47万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Master's
Dissecting the Molecular Mechanisms of the Histone Acetyltransferase/Cyclic Adenosine Monophosphate Binding Protein Interactome Using Protein-Observed Fluorine NMR
使用蛋白质观察的氟 NMR 剖析组蛋白乙酰转移酶/环单磷酸腺苷结合蛋白相互作用组的分子机制
- 批准号:
1904071 - 财政年份:2019
- 资助金额:
$ 31.47万 - 项目类别:
Standard Grant
Osmotic stress regulation and the role of cyclic di-adenosine monophosphate (c-di-AMP) in Staphylococcus aureus
金黄色葡萄球菌的渗透应激调节和环二腺苷单磷酸 (c-di-AMP) 的作用
- 批准号:
318765828 - 财政年份:2016
- 资助金额:
$ 31.47万 - 项目类别:
Research Fellowships
Novel mechanisms controlling signaling by adenosine monophosphate-activated protein kinase, central regulator of energy homeostasis
通过单磷酸腺苷激活蛋白激酶控制信号传导的新机制,能量稳态的中央调节器
- 批准号:
FT130100988 - 财政年份:2014
- 资助金额:
$ 31.47万 - 项目类别:
ARC Future Fellowships
The roles of cyclic adenosine monophosphate (cAMP) in suppressive functions of regulatory T cells
环磷酸腺苷 (cAMP) 在调节性 T 细胞抑制功能中的作用
- 批准号:
25893115 - 财政年份:2013
- 资助金额:
$ 31.47万 - 项目类别:
Grant-in-Aid for Research Activity Start-up
Molecular mechanisms of cyclic Adenosine Monophosphate (AMP) induced apoptosis
环磷酸腺苷(AMP)诱导细胞凋亡的分子机制
- 批准号:
DP110100417 - 财政年份:2011
- 资助金额:
$ 31.47万 - 项目类别:
Discovery Projects