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.
项目总结
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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{{ 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:
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