Synthetic Ligands for Modulating Bacterial Communication
用于调节细菌通讯的合成配体
基本信息
- 批准号:8628580
- 负责人:
- 金额:$ 29.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-01-01 至 2017-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAgonistAntibioticsAttenuatedBacteriaBacterial InfectionsBacterial ModelBacteriologyBasic ScienceBindingBinding SitesBiochemicalBiochemistryBiologicalBiological AssayBiologyCell DensityCellsChemicalsChronicCommunicationDNA receptorDevelopmentDiseaseEvaluationGene ExpressionGeneticGenetic TechniquesGram-Negative BacteriaGrantGrowthHumanIn VitroInfectionInterceptInterdisciplinary StudyLaboratoriesLeadLibrariesLigand BindingLigandsMediatingMethodsMicrobial BiofilmsMolecularOrganic ChemistryPathway interactionsPhenotypePlayPopulationPopulation DensityProductionPseudomonas aeruginosaPublic HealthReceptor ActivationReceptor InhibitionReporterReportingResearchResistanceResistance developmentRoleRouteSignal PathwaySignal TransductionSiteStructureStructure-Activity RelationshipSymbiosisSystemTechniquesTherapeuticTimeVirulenceVirulence FactorsWorkanalogantimicrobialbasebiomaterial developmentcell motilitychemical geneticsclinically relevantcomparativedesignhomoserine lactoneimprovedin vivoinhibitor/antagonistinsightnext generationnovelnovel therapeutic interventionpathogenpreventpublic health relevancequorum sensingreceptorresearch studyscaffoldsmall moleculetooltranscription factor
项目摘要
PROJECT SUMMARY / ABSTRACT
Quorum sensing (QS) is widespread in bacteria and plays a pivotal role in their interactions with
eukaryotic hosts. This intercellular signaling mechanism is based on small molecule ligands and their
cognate protein receptors, and allows bacteria to assess their local population densities and function
as a group. The long-term objective of the proposed research is to design, synthesize, and
characterize non-native small molecules capable of intercepting native QS signals for use as tools to
dissect the myriad roles of QS in bacterial populations and in bacteria-host associations. The
potential impact of such chemical probes is enormous, and ranges from applications in basic research
to therapeutic and biomaterials development. As many of the most notorious human pathogens use
QS to activate virulence pathways that are the origin of acute and chronic infections, including biofilm
formation, the application of QS antagonists holds significant promise as a novel antimicrobial
strategy. Such "anti-virulence" agents differ from current antibiotics because they target infectivity as
opposed to growth, and represent a paradigm shift for the treatment of bacteria-mediated disease.
QS in Gram-negative bacteria is the best characterized to date and the focus of this project. These
QS circuits are based on N-acyl L-homoserine lactone (AHL) signals and LuxR-type transcription
factors, and binding of the AHL to its target LuxR-type receptor triggers QS-controlled gene
expression at high cell densities. In earlier work, we studied the structures of LuxR-type receptor
ligand-binding sites, designed non-native ligands capable of targeting these sites, and developed
efficient synthetic routes to libraries of these compounds. Evaluation of the libraries in model
bacterial strains revealed several of the most potent synthetic antagonists and agonists of LuxR-type
QS reported to date. These results validate our overall research strategy.
Our intent now is to develop new small molecules scaffolds capable of intercepting LuxR-type QS
with improved potencies and stabilities, determine the mechanisms by which these compounds exert
their QS modulatory activities, and examine their ability to attenuate QS phenotypes in wild-type
human pathogens. During the grant period, these objectives will be pursued in three Specific Aims.
These are: (1) Design and Structural Optimization of New Synthetic QS Antagonists and Agonists, (2)
Mechanistic Analysis of LuxR-type Receptor Antagonism and Agonism by Synthetic Ligands, and (3)
Cell-Based Virulence Assays and Studies of Resistance Development to QS Antagonists. The results of
the interdisciplinary research proposed herein will provide fundamental insights into the
mechanisms of QS and ultimately could provide an approach for the development of next-
generation, anti-virulence treatments for bacterial infection.
项目概要/摘要
群体感应(QS)在细菌中广泛存在,在细菌与细菌的相互作用中发挥着关键作用。
真核宿主。这种细胞间信号传导机制基于小分子配体及其
同源蛋白质受体,并允许细菌评估其当地种群密度和功能
作为一个群体。拟议研究的长期目标是设计、综合和
表征能够拦截天然 QS 信号的非天然小分子,用作工具
剖析 QS 在细菌种群和细菌-宿主关联中的无数作用。这
此类化学探针的潜在影响是巨大的,范围涵盖基础研究的应用
治疗和生物材料的开发。由于许多最臭名昭著的人类病原体都使用
QS 激活急性和慢性感染的毒力途径,包括生物膜
的形成,QS拮抗剂的应用作为一种新型抗菌剂具有重大前景
战略。这种“抗毒力”药物与目前的抗生素不同,因为它们的目标是感染性
与生长相反,代表了治疗细菌介导疾病的范式转变。
革兰氏阴性菌的 QS 是迄今为止最好的特征,也是该项目的重点。这些
QS 电路基于 N-酰基 L-高丝氨酸内酯 (AHL) 信号和 LuxR 型转录
AHL 与其目标 LuxR 型受体的结合触发 QS 控制的基因
高细胞密度下的表达。在早期的工作中,我们研究了LuxR型受体的结构
配体结合位点,设计能够靶向这些位点的非天然配体,并开发
这些化合物库的有效合成路线。模型中库的评估
细菌菌株揭示了几种最有效的 LuxR 型合成拮抗剂和激动剂
QS 迄今报告。这些结果验证了我们的整体研究策略。
我们现在的目的是开发能够拦截 LuxR 型 QS 的新型小分子支架
通过提高效力和稳定性,确定这些化合物发挥作用的机制
它们的 QS 调节活性,并检查它们减弱野生型 QS 表型的能力
人类病原体。在拨款期间,这些目标将通过三个具体目标来实现。
这些是:(1) 新型合成 QS 拮抗剂和激动剂的设计和结构优化,(2)
合成配体对 LuxR 型受体拮抗和激动的机制分析,以及 (3)
基于细胞的毒力测定和 QS 拮抗剂耐药性发展的研究。结果
本文提出的跨学科研究将为以下问题提供基本见解:
QS 机制,最终可以为下一代的开发提供一种方法
产生,细菌感染的抗毒力治疗。
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(3)
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Helen E. Blackwell其他文献
Die Ringschluß‐Olefin‐Metathese als hocheffiziente Methode zur Synthese kovalent querverbrückter Peptide
Die Ringschlu�Olefin�Metathese als hocheffiziente Methode zur Synthese kovalent querverbrückter Peptide
- DOI:
10.1002/(sici)1521-3757(19981204)110:23<3469::aid-ange3469>3.0.co;2-a - 发表时间:
1998-12-04 - 期刊:
- 影响因子:0
- 作者:
Helen E. Blackwell;R. H. Grubbs - 通讯作者:
R. H. Grubbs
Characterization of structural elements in native autoinducing peptides and non-native analogues that permit the differential modulation of AgrC-type quorum sensing receptors inStaphylococcus aureus
- DOI:
10.1039/c5ob01735a - 发表时间:
2015-09 - 期刊:
- 影响因子:3.2
- 作者:
Yftah Tal-Gan;Monika Ivancic;Gabriel Cornilescu;Helen E. Blackwell - 通讯作者:
Helen E. Blackwell
Slippery nanoemulsion-infused porous surfaces (SNIPS): anti-fouling coatings that can host and sustain the release of water-soluble agents
- DOI:
10.1039/d1cc04645d - 发表时间:
2021-11 - 期刊:
- 影响因子:4.9
- 作者:
Harshit Agarwal;Thomas J. Polaske;Gabriel Sánchez-Velázquez;Helen E. Blackwell;David M. Lynn - 通讯作者:
David M. Lynn
Unraveling the contributions of hydrogen-bonding interactions to the activity of native and non-native ligands in the quorum-sensing receptor LasR
- DOI:
10.1039/c4ob02252a - 发表时间:
2014-11 - 期刊:
- 影响因子:3.2
- 作者:
Joseph P. Gerdt;Christine E. McInnis;Trevor L. Schell;Helen E. Blackwell - 通讯作者:
Helen E. Blackwell
Application of Ring-Closing Metathesis to the Synthesis of Rigidified Amino Acids and Peptides
闭环复分解在刚性氨基酸和肽合成中的应用
- DOI:
10.1021/ja961626l - 发表时间:
1996-10-09 - 期刊:
- 影响因子:15
- 作者:
Scott J. Miller;Helen E. Blackwell;R. Grubbs - 通讯作者:
R. Grubbs
Helen E. Blackwell的其他文献
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{{ truncateString('Helen E. Blackwell', 18)}}的其他基金
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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:
$ 29.85万 - 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:
$ 29.85万 - 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:
10598009 - 财政年份:2019
- 资助金额:
$ 29.85万 - 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:
$ 29.85万 - 项目类别:
Chemical Strategies to Modulate Intercellular Bacterial Communication
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10798787 - 财政年份:2019
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布鲁克和瓦里安光谱仪和核磁共振的使用培训
- 批准号:
7598702 - 财政年份:2007
- 资助金额:
$ 29.85万 - 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:
7548611 - 财政年份:2006
- 资助金额:
$ 29.85万 - 项目类别:
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