Chemical Strategies to Modulate Intercellular Bacterial Communication
调节细胞间细菌通讯的化学策略
基本信息
- 批准号:10598009
- 负责人:
- 金额:$ 36.88万
- 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:2019-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:Acute DiseaseAddressAdvanced DevelopmentAreaAttenuatedAwarenessBacteriaBacterial InfectionsBacteriologyBehaviorBiochemicalBiochemistryBiologyCell CommunicationCell DensityCellsChemicalsChemistryChronic DiseaseClinicalCommunicationCommunitiesDevelopmentEnvironmentFoundationsGenomicsGoalsGram-Negative BacteriaHealthHumanIndividualInfectionInterceptLaboratoriesLeadLeadershipLigandsMaintenanceMethodsMolecularOrganismOutcomePathway interactionsPopulationPositioning AttributeProcessReceptor SignalingResearchResearch Project GrantsRoleShapesSignal PathwaySignal TransductionSignaling MoleculeSystemTestingUnited States National Institutes of HealthVirulenceVisionWorkantimicrobialchemical synthesisinsightintercellular communicationmicrobialmicrobial communitymicrobiomemicrobiotanovel therapeutic interventionpathogenprogramsquorum sensingreceptorsmall moleculestructural biologytool
项目摘要
PROJECT SUMMARY/ABSTRACT
This MIRA proposal outlines an integrated research program at the interface of chemistry and biology focused
on cell-cell communication in bacteria, or “quorum sensing” (QS). QS has a major impact on human health,
with some of the most common pathogens utilizing this sensing mechanism to regulate virulence—i.e., the
ability to initiate infection—once sufficient cells have amassed to overwhelm a host. Understanding the
molecular mechanisms of QS, its role in mixed microbial communities, and its impact on both acute and
chronic disease remain pressing and unaddressed challenges in the field. For example, our understanding of
how QS signaling molecules interact with their target protein receptors to activate or inhibit QS pathways is
limited to four species in Gram-negative bacteria. Further, with an increasing awareness of the importance of
microbial communities (i.e., our “microbiomes”) to human health, it is astonishing how little we know about
the role of chemical signaling between these organisms in the maintenance (or disruption) of healthy microbial
consortia. As bacteria use simple chemical signals to regulate QS, synthetic chemists and chemical biologists
are well positioned to address these problems and other related challenges at the molecular level. With support
from the NIH over the past decade, the PI has advanced the development of synthetic ligands that modulate QS
signaling systems in Gram-negative bacteria and has shown that these ligands can strongly attenuate QS-
controlled behaviors in many pathogens. This past work situates her ideally to lead this research project.
The overall vision for this MIRA project is to build on the PI's 12-year foundation of results and leadership
in this area and apply a chemical approach to expand the understanding of QS across multiple scales—from
individual QS signal:receptor interactions to signaling in a single species to signaling within mixed bacterial
populations to interactions of the community with a host. We will achieve this vision through the pursuit of
three broad Goals: (1) the development of new small molecules capable of strongly modulating QS in Gram-
negative bacteria with high potencies, stabilities, and defined modes of action; (2) the application of these
molecules and new chemical strategies to delineate the biochemical mechanisms of QS; and (3)
characterization of the roles of QS in mixed microbial environments relevant to human health. These three
Goals will be pursued through an integration of chemical synthesis, chemical biology, bacteriology,
biochemistry, structural biology, and genomics. Studies will be performed in the PI's laboratory at the UW–
Madison and with a team of committed collaborators with expertise in QS and methods critical to this project.
The overall outcome of this project will be a drastically increased and rigorously tested understanding of QS in
bacteria and its role in biologically significant environments, and a suite of new and freely accessible research
tools for the QS field. Our findings will shape the development of new methods to treat bacterial disease and
will directly impact human health.
项目摘要/摘要
该MIRA提案概述了以化学和生物学界面的综合研究计划
关于细菌中的细胞 - 细胞通信,或“法规传感”(QS)。 QS对人类健康有重大影响,
使用某些最常见的病原体使用这种传感机制来调节病毒 - 即
启动感染的能力 - 一旦有足够的细胞积聚,以压倒宿主。了解
QS的分子机制,其在混合微生物群落中的作用及其对急性和急性的影响
慢性疾病在该领域仍在紧迫和未解决的挑战。例如,我们对
QS信号分子如何与目标蛋白受体相互作用以激活或抑制QS途径是
限制于革兰氏阴性细菌中的四种。此外,随着对重要性的意识
微生物群落(即我们的“微生物组”)对人类健康,令人惊讶的是我们对
这些生物之间化学信号在健康微生物的维持(或破坏)中的作用
财团。由于细菌使用简单的化学信号来调节QS,合成化学家和化学生物学家
可以在分子水平上解决这些问题和其他相关挑战的好处。支持
从过去十年来的NIH开始,PI已提高了调节QS的合成配体的发展
革兰氏阴性细菌中的信号传导系统,并表明这些配体可以强烈减弱QS-
许多病原体中的受控行为。过去的工作状况理想地领导这项研究项目。
这个MIRA项目的总体愿景是建立PI的成绩和领导成果的12年基础
在该领域并采用化学方法来扩展跨多个尺度的QS理解
单个QS信号:在混合细菌中单个物种中与信号传导的受体相互作用
社区与东道主的互动人群。我们将通过追求来实现这一愿景
三个广泛的目标:(1)开发能够在革兰氏体中强烈调节QS的新小分子
具有高电位,系统和定义的作用模式的负细菌; (2)这些应用
分子和新的化学策略来描述QS的生化机制; (3)
QS在与人类健康相关的混合微生物环境中的作用的表征。这三个
将通过化学合成,化学生物学,细菌学的整合来实现目标,
生物化学,结构生物学和基因组学。研究将在UW – PI的实验室中进行
麦迪逊(Madison)和一个有坚定的合作者团队在QS和方法方面具有专业知识,对该项目至关重要。
该项目的总体结果将是对QS中QS的大幅增长和严格测试
细菌及其在生物学意义的环境中的作用,以及一套新的免费可访问研究
QS字段的工具。我们的发现将塑造用于治疗细菌疾病的新方法的发展
将直接影响人类健康。
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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Helen E. Blackwell其他文献
Helen E. Blackwell的其他文献
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{{ truncateString('Helen E. Blackwell', 18)}}的其他基金
Strategies to Block Skin Wound Infection by Intercepting Bacterial Cell-to-Cell Signaling
通过拦截细菌细胞间信号传导来阻止皮肤伤口感染的策略
- 批准号:
10667239 - 财政年份:2023
- 资助金额:
$ 36.88万 - 项目类别:
Chemical Strategies to Modulate Intercellular Bacterial Communication
调节细胞间细菌通讯的化学策略
- 批准号:
9908123 - 财政年份:2019
- 资助金额:
$ 36.88万 - 项目类别:
Chemical Strategies to Modulate Intercellular Bacterial Communication
调节细胞间细菌通讯的化学策略
- 批准号:
10798787 - 财政年份:2019
- 资助金额:
$ 36.88万 - 项目类别:
Chemical Strategies to Modulate Intercellular Bacterial Communication
调节细胞间细菌通讯的化学策略
- 批准号:
10397530 - 财政年份:2019
- 资助金额:
$ 36.88万 - 项目类别:
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- 批准号:
7598702 - 财政年份:2007
- 资助金额:
$ 36.88万 - 项目类别:
Synthetic Ligands for Modulating Bacterial Communication
用于调节细菌通讯的合成配体
- 批准号:
7742173 - 财政年份:2006
- 资助金额:
$ 36.88万 - 项目类别:
Synthetic Ligands for Modulating Bacterial Communication
用于调节细菌通讯的合成配体
- 批准号:
7341065 - 财政年份:2006
- 资助金额:
$ 36.88万 - 项目类别:
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