Development of Artificial Agonists for a Bacterial Riboswitch
细菌核糖开关人工激动剂的开发
基本信息
- 批准号:7810909
- 负责人:
- 金额:$ 12.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-30 至 2011-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcidsActive SitesAffectAgonistAminesAntibiotic ResistanceAntibioticsBacteriaBacterial InfectionsBindingBiological AssayCatalysisCatalytic RNACell WallChemicalsCleaved cellCoenzymesCollaborationsCommitComplexDeuteriumDevelopmentElementsFeedbackFinancial SupportFunctional RNAFundingGene ExpressionGene Expression AlterationGenesGeneticGram-Positive BacteriaGrantGrowthHumulusHydrogenIn VitroInvestigationIonsIsotopesKineticsKnowledgeLaboratoriesLigandsManuscriptsMapsMeasurementMessenger RNAMetabolicMetabolic PathwayMetabolismMetalsPlayProcessPropertyProtonsRNAReactionReagentRecoveryRegulationRelative (related person)ReporterReporter GenesResistanceRoleStructureSystemTestingTimeUnited States National Institutes of HealthWorkanalogantimicrobial drugbasecombatdesignfightingfunctional groupglucosamine 6-phosphategraduate studentin vivoinorganic phosphateinsightmeetingsnovelnovel strategiesnucleobasenucleotide analogpathogenprospectivepublic health relevancereaction rateresearch study
项目摘要
DESCRIPTION (provided by applicant): Antibiotic Properties of Artificial Agonists for a Bacterial Riboswitch Notice Number NOT-OD-09-058 Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications The emergence of antibiotic resistance has required that new approaches be applied in order to effectively fight a host of medically relevant bacterial infections. The currently used, imprecise antibiotics, need to be replaced with novel, rigorous, and safe treatments in order to combat the evolved bacterium of today. One way to destroy bacteria is to target one of their most essential processes, metabolism. The discovery of RNA structural elements, termed riboswitches, that bind cellular metabolites and control expression of essential metabolic genes provides a unique and distinct target for development of artificial agonists to fight bacterial infections. Riboswitches are found in non-coding regions of messenger RNAs, and gene expression is modulated when metabolite binds directly to the RNA. Many riboswitches repress expression of nearby genes involved in the synthesis of the metabolite, providing an efficient feedback mechanism of genetic control. One particular riboswitch (the glmS riboswitch) binds to glucosamine-6-phosphate (GlcN6P), a building block of the cell wall in Gram-positive bacteria, and undergoes self-cleavage resulting in inactivity of the mRNA. The amine functionality of GlcN6P seems to be directly involved in RNA catalysis, whereas the phosphate may play a role in ligand recognition. In order to develop effective artificial agonists/antibiotics that target the glmS riboswitch, an understanding of the structural and functional details of the riboswitch- metabolite complex is essential. The aims of the original grant were focused on (1) investigating the structural and catalytic roles of metal ions in the glmS riboswitch, (2) deciphering ligand recognition by the glmS riboswitch, and (3) designing non-natural agonists with the ability to stimulate glmS riboswitch self-cleavage and control gene expression. Aim 1 has been completed and Aim 2 is nearly finished. In regards to Aim 3, we have begun to test a small number of non-natural ligands, one of which does support glmS self-cleavage. This revision will significantly expand the scope of Aim 3 of the original grant in order to include additional ligand analog syntheses and bacterial growth experiments to test the antibiotic properties of the synthesized artificial agonists. Further expansion of the project will include an investigation of the mechanism of the self-cleavage reaction using kinetic isotope experiments. Both lines of experimentation will further aid in rational design of non-natural metabolite-like compounds that can function as agonists/antibiotics to halt bacterial growth through alteration of gene expression.
PUBLIC HEALTH RELEVANCE: The threat of bacterial infections due to lack of effective antibiotics has come to the forefront as these pathogens become resistant to almost every antibiotic available to the public. The need is great for new classes of anti-microbial agents that target different, but specific and essential, metabolic pathways, such as those which utilize riboswitches to control gene expression. Structure-function and mechanistic studies of riboswitches have enabled detailed studies of ligand recognition by RNA as well as rational design of non-natural agonists that ultimately could function as antibiotics.
描述(由申请人提供):细菌核糖开关人工激动剂的抗生素特性 公告编号 NOT-OD-09-058 公告标题:NIH 宣布恢复法案资金可用于竞争性修订申请 抗生素耐药性的出现要求采用新方法应用以有效对抗许多医学相关的细菌感染。目前使用的不精确的抗生素需要用新颖、严格且安全的治疗方法取代,以对抗当今进化的细菌。消灭细菌的一种方法是针对细菌最重要的过程之一——新陈代谢。 RNA 结构元件(称为核糖开关)的发现,可以结合细胞代谢物并控制必需代谢基因的表达,为开发抗细菌感染的人工激动剂提供了独特且独特的靶标。核糖开关存在于信使 RNA 的非编码区,当代谢物直接与 RNA 结合时,基因表达就会受到调节。许多核糖开关抑制附近参与代谢物合成的基因的表达,提供有效的遗传控制反馈机制。一种特殊的核糖开关(glmS 核糖开关)与 6-磷酸葡萄糖胺 (GlcN6P)(革兰氏阳性细菌细胞壁的组成部分)结合,并经历自我裂解,导致 mRNA 失活。 GlcN6P 的胺官能团似乎直接参与 RNA 催化,而磷酸盐可能在配体识别中发挥作用。为了开发针对 glmS 核糖开关的有效人工激动剂/抗生素,了解核糖开关-代谢物复合物的结构和功能细节至关重要。最初资助的目的集中在(1)研究金属离子在glmS核糖开关中的结构和催化作用,(2)破译glmS核糖开关的配体识别,以及(3)设计能够刺激 glmS 核糖开关自我切割并控制基因表达。目标1已经完成,目标2即将完成。关于目标 3,我们已经开始测试少量非天然配体,其中之一确实支持 glmS 自裂解。此次修订将显着扩大原始资助目标 3 的范围,以包括额外的配体类似物合成和细菌生长实验,以测试合成的人工激动剂的抗生素特性。该项目的进一步扩展将包括利用动力学同位素实验研究自裂解反应的机制。这两条实验线将进一步有助于合理设计非天然代谢物类化合物,这些化合物可以充当激动剂/抗生素,通过改变基因表达来阻止细菌生长。
公共卫生相关性:由于缺乏有效的抗生素而导致的细菌感染威胁已成为首要问题,因为这些病原体对公众可用的几乎所有抗生素都产生了耐药性。非常需要针对不同但特定且重要的代谢途径的新型抗微生物剂,例如利用核糖开关控制基因表达的途径。核糖开关的结构功能和机制研究使得对RNA配体识别的详细研究以及最终可用作抗生素的非天然激动剂的合理设计成为可能。
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 }}
JULIANE K STRAUSS-SOUKUP其他文献
JULIANE K STRAUSS-SOUKUP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('JULIANE K STRAUSS-SOUKUP', 18)}}的其他基金
Examination of Ornithine Decarboxylase Antizyme RNA Structure and Function from Various Organisms for the Development of Antibiological Agents
检查不同生物体的鸟氨酸脱羧酶抗酶 RNA 结构和功能,用于开发抗生素
- 批准号:
10730595 - 财政年份:2023
- 资助金额:
$ 12.99万 - 项目类别:
Development of Artificial Agonists for a Bacterial Riboswitch
细菌核糖开关人工激动剂的开发
- 批准号:
7247818 - 财政年份:2007
- 资助金额:
$ 12.99万 - 项目类别:
Antibiotic Properties of Artificial Agonists for a Bacterial Riboswitch
细菌核糖开关人工激动剂的抗生素特性
- 批准号:
7980700 - 财政年份:2007
- 资助金额:
$ 12.99万 - 项目类别:
相似海外基金
Mechanisms of HIV fitness and drug resistance inferred from high-resolution molecular dynamics and sequence co-variation models
从高分辨率分子动力学和序列共变模型推断出 HIV 适应性和耐药性的机制
- 批准号:
10750627 - 财政年份:2023
- 资助金额:
$ 12.99万 - 项目类别:
Actions of spiropyrimidinetriones against bacterial type II topoisomerases
螺嘧啶三酮对细菌 II 型拓扑异构酶的作用
- 批准号:
10750473 - 财政年份:2023
- 资助金额:
$ 12.99万 - 项目类别:
Characterization of JT-4-173, a Potent Antiviral that Inhibits HIV-1 by a Novel Mechanism of Action
JT-4-173 的表征,一种通过新颖作用机制抑制 HIV-1 的强效抗病毒药物
- 批准号:
10762518 - 财政年份:2023
- 资助金额:
$ 12.99万 - 项目类别:
Novel Therapeutics for Heart Failure: Modified, Water-Soluble Caveolin-1 Scaffolding Domain Peptides with Improved Characteristics for Drug Development
心力衰竭的新型疗法:修饰的水溶性 Caveolin-1 支架结构域肽,具有改进的药物开发特性
- 批准号:
10599654 - 财政年份:2023
- 资助金额:
$ 12.99万 - 项目类别:
Structural and functional studies of glycosyl hydrolases governing Vibrio biofilm dispersal
控制弧菌生物膜分散的糖基水解酶的结构和功能研究
- 批准号:
10795423 - 财政年份:2023
- 资助金额:
$ 12.99万 - 项目类别: