权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
Allison Lopatkin
金额：
$ 23.78万
依托单位：
BARNARD COLLEGE
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：
https://reporter.nih.gov/project-details/10291392
关键词：
Antibiotic Resistance Bacteria Biochemical Pathway Cells Characteristics Clinical Code Communities Complement Complex Cost Measures Data Defect Distant Environment Escherichia coli Evolution Exhibits Foundations Future Gene Expression Genes Genetic Genetic Determinism Genetic Transcription Genomics Goals Growth Horizontal Gene Transfer Hour Human Microbiome In Situ Individual Intervention Klebsiella pneumoniae Laboratories Length Measurement Metabolic Metabolic Pathway Metabolism Methods Microbiology Minority Modeling Molecular Nature Pathogenesis Phenotype Physiological Plasmids Play Population Population Dynamics Prevalence Protocols documentation Public Health Research Role Sampling Series Soil Son of Sevenless Proteins Testing Time Validation Virulence Water Work base combat cost density environmental stressor experimental study fitness insight knockout gene microbial microbial community multidisciplinary network models novel pathogen plasmid DNA reproductive success response success tool transcription factor transcriptome sequencing transcriptomics undergraduate student whole 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：
ISME JOURNAL
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.