Advancing ribosome-targeting antibacterial peptides with a unique mechanism of action
以独特的作用机制推进核糖体靶向抗菌肽
基本信息
- 批准号:10443921
- 负责人:
- 金额:$ 45.43万
- 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:2022-02-08 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:Acinetobacter baumanniiAffectAmino Acid SequenceAmino AcidsAnti-Bacterial AgentsAntibioticsBacteriaBindingBiochemistryBiologicalBypassCellsChemistryClinicalComplexCrystallizationDataDevelopmentDrosophila genusEscherichia coliEventFutureGene LibraryGenomeGenomicsGoalsGram-Negative BacteriaGram-Positive BacteriaGrowthHybridsInfectionLaboratoriesModelingNaturePenetrationPeptide SynthesisPeptidesPharmaceutical PreparationsProlinePropertyProtein BiosynthesisProtein Synthesis InhibitorsProteinsPublishingReagentResearchResolutionRibosomesRoentgen RaysSpecificityStaphylococcus aureusStructureTerminator CodonTestingTransfer RNATranslationsVariantWorkantimicrobial peptidebasecell growthclinical developmentclinically relevantcomparativedesignflyhuman pathogenimprovedinfancyinhibitorknowledge basenovelpathogenpeptide chemical synthesispeptide drugpreventrational designrelease factorscreeningtherapeutic developmenttooluptakewhole genome
项目摘要
Project Summary
Apidaecin (Api) and Drosocin (Dro), are proline-rich antimicrobial peptides (PrAMPs) produced by honeybees and
fruit flies, respectively, which share a unique mechanism of action. Our previous studies of Api showed that upon entering
Gram-negative bacterial cells through the SbmA transporter, Api binds in the exit tunnel of ribosomes that have just released
the newly made protein and arrests the ribosomes at stop codons by trapping the associated tRNA and release factor. As
such, Api represents the first-ever described specific inhibitor of translation termination. Our subsequent whole-genome
studies revealed that arresting terminating ribosomes triggers several downstream events that accentuate the inhibitory
action of this PrAMP, including ribosome queuing and readthrough of stop codons. Our preliminary data indicate that Dro,
despite its distinct amino acid sequence, inhibits the termination step of translation as well, by a mechanism likely resembling
that of Api. Their idiosyncratic mode of binding to the target, the unique mechanism of action, and the triggering of
downstream effects harmful for the bacterial cell, make these antibacterial peptides an attractive model for developing novel
antibiotics. Furthermore, the biological nature of these PrAMPs opens unique opportunities for their screening and
optimization by generating hundreds of thousands of peptide variants directly in bacterial cells.
In the current proposal we will use the combined effort of three laboratories with expertise in biochemistry and
genomics of ribosomal antibiotics, in peptide chemistry and in structural analysis of ribosome-antibiotic complexes to
advance the fundamental understanding of the mechanism of action of Api- and Dro-like translation termination inhibitors
and identify derivatives with superior on-target activity and expanded spectrum of antibacterial action. In order to achieve
these goals we will test arrays of Api and Dro variants in bacterial cells by the tunable expression of peptide gene libraries,
determine high-resolution X-ray crystal structures of ribosome-peptide complexes, and employ rational structure-based
design to generate via chemical synthesis peptide variants with superior properties. Specifically: In Aim 1, we will identify
Api-derived peptides with improved activity upon ribosomes from Gram-negative and Gram-positive pathogens. In Aim 2,
the spectrum of action of Api-like peptides will be expanded by bypassing the necessity for uptake by the SbmA transporter.
Finally, in Aim 3, we will analyze the ribosome binding and mechanism of action of Dro-like peptides and use comparative
analysis to identify the key features that define the class of antimicrobial peptides that target translation termination. The
three Aims are tightly interconnected but completely independent from each other.
The reagents and tools that will be generated in the course of the proposed work are aimed to serve as leads for
future clinical development. Importantly, the results obtained in the proposed studies will significantly advance the
fundamental understanding of the properties and mechanisms of action of PrAMPs and will stimulate the progress of the
field of ribosome-targeting antibacterial peptides, which currently is still in its infancy.
项目摘要
Apidaecin(API)和Drosocin(Dro)是由蜜蜂产生的富含脯氨酸的抗菌肽(PrAMP),
果蝇,它们有着独特的作用机制。我们之前对API的研究表明,
在革兰氏阴性细菌细胞中,API通过SbmA转运蛋白结合在刚刚释放的核糖体的出口通道中,
新产生的蛋白质,并通过捕获相关的tRNA和释放因子将核糖体捕获在终止密码子处。作为
因此,API代表了第一个描述的翻译终止的特异性抑制剂。我们后来的全基因组
研究表明,阻止终止核糖体会触发几个下游事件,
这种PrAMP的作用,包括核糖体排队和终止密码子的通读。我们的初步数据显示德罗,
尽管其氨基酸序列不同,但也通过类似于
这是API。它们与靶点结合的特异性模式、独特的作用机制和
下游效应对细菌细胞有害,使这些抗菌肽成为开发新型抗菌肽的有吸引力的模型。
抗生素此外,这些PrAMP的生物学性质为它们的筛选提供了独特的机会,
通过直接在细菌细胞中产生数十万种肽变体来优化。
在目前的提案中,我们将利用三个具有生物化学专业知识的实验室的共同努力,
核糖体抗生素基因组学、肽化学和核糖体-抗生素复合物的结构分析,
推进对API和Dro样翻译终止抑制剂作用机制的基本理解
并鉴定具有上级的靶向活性和广谱抗菌作用的衍生物。为了实现
为了这些目的,我们将通过肽基因文库的可调表达来测试细菌细胞中API和Dro变体的阵列,
确定核糖体-肽复合物的高分辨率X射线晶体结构,并采用合理的基于结构的
设计以通过化学合成产生具有上级性质的肽变体。具体而言:在目标1中,我们将确定
对来自革兰氏阴性和革兰氏阳性病原体的核糖体具有改进活性的Api衍生肽。在目标2中,
Api样肽的作用谱将通过绕过SbmA转运蛋白摄取的必要性而扩展。
最后,在目标3中,我们将分析Dro样肽的核糖体结合和作用机制,并使用比较
分析以鉴定定义靶向翻译终止的抗微生物肽类的关键特征。的
三个目标紧密相连,但又完全独立。
在拟议的工作过程中将产生的试剂和工具旨在作为以下方面的线索:
未来的临床发展。重要的是,在拟议的研究中获得的结果将大大推进
对PrAMP的性质和作用机制的基本理解,并将促进
核糖体靶向抗菌肽领域,目前仍处于起步阶段。
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 }}
ALEXANDER S MANKIN其他文献
ALEXANDER S MANKIN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('ALEXANDER S MANKIN', 18)}}的其他基金
Advancing ribosome-targeting antibacterial peptides with a unique mechanism of action
以独特的作用机制推进核糖体靶向抗菌肽
- 批准号:
10569098 - 财政年份:2022
- 资助金额:
$ 45.43万 - 项目类别:
Advancing ribosome-targeting antibacterial peptides with a unique mechanism of action
以独特的作用机制推进核糖体靶向抗菌肽
- 批准号:
10436039 - 财政年份:2021
- 资助金额:
$ 45.43万 - 项目类别:
Equipment Supplement Request for Purchasing Amersham Typhoon RGB Phosphorimager (for R35GM127134)
购买 Amersham Typhoon RGB 荧光成像仪(适用于 R35GM127134)的设备补充申请
- 批准号:
10386084 - 财政年份:2018
- 资助金额:
$ 45.43万 - 项目类别:
Exploiting antibiotics to understand the ribosome and translation
利用抗生素来了解核糖体和翻译
- 批准号:
10366000 - 财政年份:2018
- 资助金额:
$ 45.43万 - 项目类别:
Exploiting antibiotics to understand the ribosome and translation
利用抗生素来了解核糖体和翻译
- 批准号:
9897557 - 财政年份:2018
- 资助金额:
$ 45.43万 - 项目类别:
Context-specific action of antibiotics targeting the catalytic center of the bacterial ribosome
针对细菌核糖体催化中心的抗生素的特定作用
- 批准号:
9158354 - 财政年份:2016
- 资助金额:
$ 45.43万 - 项目类别:
Context-specific action of antibiotics targeting the catalytic center of the bacterial ribosome
针对细菌核糖体催化中心的抗生素的特定作用
- 批准号:
9332339 - 财政年份:2016
- 资助金额:
$ 45.43万 - 项目类别:
Molecular mechanisms of action of macrolide antibiotics
大环内酯类抗生素的分子作用机制
- 批准号:
8482422 - 财政年份:2013
- 资助金额:
$ 45.43万 - 项目类别:
Molecular mechanisms of action of macrolide antibiotics
大环内酯类抗生素的分子作用机制
- 批准号:
8640960 - 财政年份:2013
- 资助金额:
$ 45.43万 - 项目类别:
Programmed translation arrest controlled by nascent peptides and antibiotics
由新生肽和抗生素控制的程序化翻译停滞
- 批准号:
8917273 - 财政年份:2012
- 资助金额:
$ 45.43万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 45.43万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 45.43万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 45.43万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 45.43万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 45.43万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 45.43万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 45.43万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 45.43万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 45.43万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 45.43万 - 项目类别:
Grant-in-Aid for Early-Career Scientists