Virus-host interactions and microbial ecology
病毒-宿主相互作用和微生物生态学
基本信息
- 批准号:10394302
- 负责人:
- 金额:$ 56.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-05-06 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAnimal ModelAntibiotic ResistanceAntibioticsBacteriaBacteriophage muCellsCessation of lifeChemoresistanceChromatin LoopChromosomesComplexDrug EffluxEcologyEscherichia coliEvolutionExposure toGene ExpressionGene FamilyGene RearrangementGenomeGenomicsGram-Negative BacteriaGrantGrowthHU ProteinHumanIncubatorsMalignant NeoplasmsMeasuresMembraneMicrobiologyMotorOperonPaste substancePathway interactionsPopulationProductionPropertyPumpResearchResolutionRibosomal RNASalmonellaSpecificitySurfaceantibiotic tolerancecell growthcell killingcondensinefflux pumpgenetic resistancegenomic locusin vivomicrobialnon-geneticperiplasmrefractory cancerresponsetoolvirus host interaction
项目摘要
Virus-host interactions and microbial ecology
This proposal encompasses two very different aspects of microbiology, both at cellular and group levels. (1)
Probing E. coli genome organization and chromosome dynamics using phage Mu transposition as our tool. Mu
transposition is unique not only in its high efficiency and lack of target specificity, but also in its transposition
mechanism, which occurs by a nick-join rather than a cut-and-paste pathway. In the last grant period, we
exploited these properties to measure in vivo rates of interactions between genomic loci in E. coli, and studied
their proximity using new statistical tools. In a complete reversal of the current view of the E. coli genome,
our analysis has revealed an uncompartmentalized, well-mixed genome, where transpositions occur freely
between all measured loci. The analysis also revealed that several gene families (for example, six widely
distributed ribosomal RNA operons) show `clustering' i.e. strong 3D co-localization regardless of linear
genomic distance. The activities of the SMC/condensin complex MukBEF and the nucleoid-compacting protein
HU-α are responsible for these properties. We propose to explore these phenomena to obtain a high-
resolution view of genome organization, and to understand how it influences gene expression in bacteria. (2)
Dissecting the mechanism of antibiotic tolerance under two specific growth conditions: swarming (moving as a
collective), and c-di-GMP synthesis catalyzed by the diguanulate cyclase YfiN. Swarming bacteria can
withstand exposure to antibiotics at concentrations that are lethal to their planktonic counterparts. We call this
swarming-specific (non-genetic) resistance, SR. In the last grant period, we discovered that death of a sub-
population as a result of antibiotic-induced killing, is beneficial to the swarm in promoting SR. Introduction of
pre-killed cells into a swarm indeed enhanced SR, allowing us to purify the SR factor from killed cells of both E.
coli and Salmonella. We identified the SR factor to be AcrA, a periplasmic component of a tripartite RND efflux
pump; the outer membrane component of this pump, TolC, is also a constituent of multiple drug efflux pumps.
We showed that AcrA stimulates drug efflux in live cells by interacting with TolC from the outside, activating
efflux in the short term, and inducing the expression of other classes of efflux pumps in the long term, thus
amplifying the response and establishing SR. We have called this phenomenon `necrosignaling', and
discovered species-specific necrosignaling in both Gram-positive and Gram-negative bacteria. We also
discovered that production of c-di-GMP by the specific cyclase YfiN, arrests cell growth to promote an
antibiotic-tolerant persister-like state. We propose to explore both these responses further. Given that non-
genetic resistance is a known incubator for evolving genetic resistance, our findings are relevant to the current
widespread emergence of genetic resistance to antibiotics, and may be relevant to chemotherapy-resistant
cancers, which efflux the drugs prior to acquisition of genetic resistance.
病毒-宿主相互作用和微生物生态学
该提案涵盖了微生物学的两个截然不同的方面,即细胞水平和群体水平。 (1)
使用噬菌体 Mu 转座作为我们的工具探测大肠杆菌基因组组织和染色体动力学。亩
转座的独特之处不仅在于它的高效性和缺乏靶标特异性,还在于它的转座
机制,它是通过缺口连接而不是剪切和粘贴途径发生的。在上一个资助期内,我们
利用这些特性来测量大肠杆菌基因组位点之间相互作用的体内速率,并研究
使用新的统计工具来确定它们的接近程度。完全颠覆了目前对大肠杆菌基因组的看法,
我们的分析揭示了一个非区室化、充分混合的基因组,其中转座可以自由发生
所有测量的位点之间。分析还揭示了几个基因家族(例如,六个广泛使用的基因家族)
分布式核糖体 RNA 操纵子)显示“聚类”,即强 3D 共定位,无论线性如何
基因组距离。 SMC/凝缩蛋白复合物 MukBEF 和核仁压缩蛋白的活性
HU-α 负责这些特性。我们建议探索这些现象以获得高
基因组组织的分辨率视图,并了解它如何影响细菌中的基因表达。 (2)
剖析两种特定生长条件下的抗生素耐受机制:集群(作为
集体),以及由二鸟酸环化酶 YfiN 催化的 c-di-GMP 合成。蜂拥而至的细菌可以
能够承受对浮游生物致命浓度的抗生素暴露。我们称之为
群体特异性(非遗传)抗性,SR。在上一个拨款期间,我们发现一名子成员的死亡
群体由于抗生素引起的杀戮,有利于群体促进SR。简介
将预先杀死的细胞放入群体中确实增强了 SR,使我们能够从大肠杆菌和大肠杆菌的杀死细胞中纯化 SR 因子。
大肠杆菌和沙门氏菌。我们确定了 SR 因子是 AcrA,它是 RND 三方流出的周质成分
泵;该泵的外膜组件 TolC 也是多个药物流出泵的组成部分。
我们发现 AcrA 通过与外部的 TolC 相互作用来刺激活细胞中的药物流出,激活
efflux in the short term, and inducing the expression of other classes of efflux pumps in the long term, thus
放大响应并建立 SR。我们将这种现象称为“坏死信号”,并且
在革兰氏阳性和革兰氏阴性细菌中发现了物种特异性的坏死信号。我们也
发现特定环化酶 YfiN 产生 c-di-GMP,阻止细胞生长,从而促进
抗生素耐受的持续状态。我们建议进一步探讨这两种应对措施。鉴于非
遗传抗性是已知的遗传抗性进化的孵化器,我们的发现与当前的相关
对抗生素的遗传耐药性广泛出现,可能与化疗耐药有关
癌症,在获得遗传抗性之前排出药物。
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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Rasika M Harshey其他文献
Rasika M Harshey的其他文献
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{{ truncateString('Rasika M Harshey', 18)}}的其他基金
Accelerated evolution of antibiotic resistance in a bacterial swarm
细菌群中抗生素耐药性的加速进化
- 批准号:
10177564 - 财政年份:2021
- 资助金额:
$ 56.08万 - 项目类别:
Accelerated evolution of antibiotic resistance in a bacterial swarm
细菌群中抗生素耐药性的加速进化
- 批准号:
10377986 - 财政年份:2021
- 资助金额:
$ 56.08万 - 项目类别:
Virus-host interactions and microbial ecology
病毒-宿主相互作用和微生物生态学
- 批准号:
10161363 - 财政年份:2016
- 资助金额:
$ 56.08万 - 项目类别:
Virus-host interactions and microbial ecology
病毒-宿主相互作用和微生物生态学
- 批准号:
10612754 - 财政年份:2016
- 资助金额:
$ 56.08万 - 项目类别:
Virus-host interactions and microbial ecology
病毒-宿主相互作用和微生物生态学
- 批准号:
9924555 - 财政年份:2016
- 资助金额:
$ 56.08万 - 项目类别:
Virus-host interactions and microbial ecology
病毒-宿主相互作用和微生物生态学
- 批准号:
9070973 - 财政年份:2016
- 资助金额:
$ 56.08万 - 项目类别:
FlhE as a probe for the flagellar Type III secretion pore
FlhE 作为鞭毛 III 型分泌孔的探针
- 批准号:
8698613 - 财政年份:2014
- 资助金额:
$ 56.08万 - 项目类别:
FlhE as a probe for the flagellar Type III secretion pore
FlhE 作为鞭毛 III 型分泌孔的探针
- 批准号:
8911770 - 财政年份:2014
- 资助金额:
$ 56.08万 - 项目类别:
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