Establishing a mechanistic basis for the plasmid acquisition cost
建立质粒获取成本的机制基础
基本信息
- 批准号:10291392
- 负责人:
- 金额:$ 23.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:Antibiotic ResistanceBacteriaBiochemical PathwayCellsCharacteristicsClinicalCodeCommunitiesComplementComplexCost MeasuresDataDefectDistantEnvironmentEscherichia coliEvolutionExhibitsFoundationsFutureGene ExpressionGenesGeneticGenetic DeterminismGenetic TranscriptionGenomicsGoalsGrowthHorizontal Gene TransferHourHuman MicrobiomeIn SituIndividualInterventionKlebsiella pneumoniaeLaboratoriesLengthMeasurementMetabolicMetabolic PathwayMetabolismMethodsMicrobiologyMinorityModelingMolecularNaturePathogenesisPhenotypePhysiologicalPlasmidsPlayPopulationPopulation DynamicsPrevalenceProtocols documentationPublic HealthResearchRoleSamplingSeriesSoilSon of Sevenless ProteinsTestingTimeValidationVirulenceWaterWorkbasecombatcostdensityenvironmental stressorexperimental studyfitnessinsightknockout genemicrobialmicrobial communitymultidisciplinarynetwork modelsnovelpathogenplasmid DNAreproductive successresponsesuccesstooltranscription factortranscriptome sequencingtranscriptomicsundergraduate studentwhole genome
项目摘要
Project Summary/Abstract
This project will investigate the previously understudied phenomenon termed plasmid acquisition cost, in the
context of horizontal gene transfer (HGT). Plasmid transfer is a dominant way that pathogens adapt to
environmental stressors. These plasmids often exert a sustained burden on cells, associated with continued
expression of plasmid genes, known as the plasmid fitness cost. They also induce a complementary,
independent, transient burden reflective of the metabolic adaptation immediately following plasmid acquisition.
However, whereas fitness costs are well-studied, the mechanistic factors underlying these transient
effects, referred to as the plasmid acquisition costs, are currently unknown. This information is critical to
developing fundamental insights into pathogen dynamics and potential downstream interventional strategies.
Based on our preliminary data, our central hypothesis is that acquisition costs arise as a result of metabolic
dysregulation immediately following plasmid transfer. We will investigate this hypothesis with two Specific Aims:
(1) We will elucidate the transcriptional basis of the plasmid acquisition cost, by undertaking a detailed
characterization of the well-characterized RP4 conjugative plasmid in a standard laboratory Escherichia coli
strain; we note that our preliminary work illustrating the existence and extent of acquisition costs was
originally done using this combination. Specifically, we established a novel experimental protocol that reliably
quantifies the growth defect in new plasmid recipients. Here, we will pair time series RNA-seq measurements
with metabolic modeling to elucidate the metabolic dysregulation that occurs immediately following plasmid
acquisition; we will validate these results using a rationally selected set of gene knockout strains and
representative plasmids. Overall, this will establish a mechanistic explanation for observed acquisition costs.
(2) We will determine the genetic determinants of the acquisition cost in diverse plasmids, using naturally
relevant plasmids and strains isolated from both environmental and clinical samples, as well as standard
laboratory plasmids. Specifically, we will leverage available whole genome sequences with assembled
plasmids from our collaborators, along with the corresponding samples, to isolate plasmids from two species:
E. coli and Klebsiella pneumoniae. We will then quantify acquisition costs for each plasmid; multiple variable
regression will be used to understand which plasmid characteristics are most predictive of observed
acquisition costs. This will result in the first rigorous quantification of plasmid acquisition costs in naturally
occurring environmental and clinical plasmids. Beyond demonstrating the generality of this phenomenon,
these results will serve as the foundation for predicting and modulating HGT dynamics in more complex
populations. Moreover, all plasmids will be made available, which will serve as an invaluable research and
educational tool throughout the wider academic community.
项目总结/文摘
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Metabolic genes on conjugative plasmids are highly prevalent in Escherichia coli and can protect against antibiotic treatment.
- DOI:10.1038/s41396-022-01329-1
- 发表时间:2023-01
- 期刊:
- 影响因子:11
- 作者:Palomino, Alana;Gewurz, Danya;DeVine, Lela;Zajmi, Ujana;Moralez, Jenifer;Abu-Rumman, Fatima;Smith, Robert P.;Lopatkin, Allison J.
- 通讯作者:Lopatkin, Allison J.
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Allison Lopatkin其他文献
Allison Lopatkin的其他文献
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{{ truncateString('Allison Lopatkin', 18)}}的其他基金
Determinants underlying horizontal gene transfer-mediated pathogen success
水平基因转移介导的病原体成功的决定因素
- 批准号:
10713094 - 财政年份:2023
- 资助金额:
$ 23.78万 - 项目类别:
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