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
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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