Plasmid-mediated Quinolone Resistance
质粒介导的喹诺酮类耐药
基本信息
- 批准号:8695968
- 负责人:
- 金额:$ 41.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-01-01 至 2019-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAlanineAlgaeAntibiotic ResistanceBacteriaBacterial ChromosomesBindingBiological ModelsCellsChimeric ProteinsChromosome DeletionChromosomesCiprofloxacinCitrobacterDNADNA GyraseDNA Topoisomerase IVDNA-Binding ProteinsDeletion MutationDissectionElementsEnzyme InhibitionEnzymesEscherichia coliFamilyFluoroquinolonesGene ExpressionGene LibraryGene ProteinsGenesGenomeGram-Negative BacteriaGrowthHabitatsHomologous GeneHumanHybridsIntegronsKnock-outLacZ GenesLibrariesLinkMass Spectrum AnalysisMeasuresMediatingMedicalMobile Genetic ElementsMulti-Drug ResistanceMultidrug Resistance GeneMutationNatureOrganismPathway interactionsPharmaceutical PreparationsPhysiologicalPlasmidsPositioning AttributePredispositionPrincipal InvestigatorProductionProtein FamilyProteinsPublic HealthQuinolonesRegulationRegulatory ElementRegulatory PathwayReporterResistanceShewanellaSiteSon of Sevenless ProteinsStressStructureStructure-Activity RelationshipSubgroupSystemTestingTopoisomeraseToxic effectToxinVibrioWorkaminoglycoside 6&apos-N-acetyltransferaseantimicrobialantimicrobial drugbacterial resistancebaseclinically significantcrosslinkefflux pumpin vivomutantnovelpathogenprogramsprotein protein interactionpublic health relevancequinolone resistanceresearch studyresistance mechanismresistance mutationthree dimensional structure
项目摘要
DESCRIPTION (provided by applicant): Fluoroquinolones, such as ciprofloxacin, have been very useful antimicrobial agents because they are highly potent, active against a wide range of bacteria, and relatively non-toxic. Their broad use, however, has been followed by rising rates of resistance. Quinolone resistance has traditionally been understood to arise either by mutations that alter DNA gyrase and topoisomerase IV, enzymes that are the targets for quinolone action, or by mutations that increase expression of efflux pumps that actively eliminate the agents from the cell. Neither type of resistance has been transmissible since both are due to mutations on the bacterial chromosome. Hence, it came as a surprise when plasmid-mediated quinolone resistance was discovered in 1998. Three distinct mechanisms for such resistance are known: target protection by pentapeptide repeat proteins of the Qnr family that bind gyrase and may act in part as DNA mimics, quinolone inactivation by a mutant aminoglycoside 6' N-acetyltransferase [Aac(6')-Ib-cr], and provision of new systems for quinolone efflux. Each mechanism confers low-level resistance but facilitates selection of higher level, clinically significant resistance. The Qnr family is largest group with QnrA, QnrB, QnrS, QnrC, and QnrD subgroups and is now distributed worldwide with the qnr genes generally present within integrons on multidrug resistance plasmids. This renewal application builds on our prior studies to obtain a deeper and more detailed understanding of the resistance due to Qnr proteins. Under Specific Aim 1, based on our mutant Qnr studies we propose to perform site-specific cross linking of key residues of Qnr B with gyrase and analysis of sites of linkage by mass spectrometry. Bacterial 2-hybrid studies will also be used to evaluate binding of specific QnrB and gyrase mutants for their interactions in intact cells. Under Specific Aim 2, we propose to evaluate the native functions of qnr genes and a novel pathway of regulation of qnrS expression. Having excluded Qnr protection of natural gyrase toxins CcdB and ParE, we will next evaluate its protection from natural gyrase toxin MccB17 using plasmid constructs with graded expression of toxin and Qnr. We will also construct deletions of the native homologs qnrA and qnrS in Shewanella algae and Vibrio splendidus, the respective reservoir organisms and test for differences in quinolone susceptibility and growth under environmental conditions relevant for their native habitats. We will also construct a qnrS-lacZ transcriptional fusion to screen an E. coli transposon mutant library for genes necessary for the SOS-independent induction of qnrS by ciprofloxacin. Under Specific Aim 3, we propose to assess Qnr interactions with other proteins by testing the effects of qnr on expression of other E. coli genes in a transcripitional microarray with confirmation in the native organisms and by coimmunoprecipitation experiments for direct identification of binding partners with mass spectrometry analysis.
描述(由申请人提供):氟喹诺酮类(例如环丙沙星)是非常有用的抗菌剂,因为它们非常有效,对广泛的细菌且相对无毒。然而,它们的广泛使用之后,阻力率上升。传统上,奎诺酮的抗性是通过改变DNA陀螺酶和拓扑异构酶IV的突变,即是喹诺酮类作用的靶标的突变,或者是通过增加积极地消除了从细胞中消除剂的外排泵表达的突变。两种类型的耐药性均可传播,因为两者都是由于细菌染色体上的突变引起的。因此,当1998年发现质粒介导的喹诺酮耐药性时,这是一个令人惊讶的令人惊讶的。这种抵抗的三种不同的机制是已知的:QNR家族的五肽重复蛋白的靶标的靶保护,该蛋白质结合旋酶结合并可能在某种程度上充当DNA模拟物,Quinolone Mimics通过突变氨基氨基糖酶6'n-accosetyyltranterys 6'n-accietyltranterymics灭菌。 [AAC(6') - IB-CR],以及为奎诺酮外排提供的新系统。每种机制都赋予低级电阻,但有助于选择更高水平,临床上显着的阻力。 QNR家族是QNRA,QNRB,QNRS,QNRC和QNRD子组的最大群体,现在在全球范围内与QNR基因分布在多药抗性质粒上。这种更新应用是基于我们先前的研究,以获得对QNR蛋白引起的抗性的更深入,更详细的理解。在特定目标1下,基于我们的突变QNR研究,我们建议对QNR B的关键残基进行特定于地点的交叉连接,并通过质谱法分析链接位点。细菌2杂交研究还将用于评估特定QNRB和GYRASE突变体在完整细胞中相互作用的结合。在特定目标2下,我们建议评估QNR基因的天然功能和QNRS表达调节的新途径。在排除了天然回旋糖毒素CCDB和PARE的QNR保护之后,我们接下来将使用具有毒素和QNR分级表达的质粒构建体来评估其免受天然Gyrase毒素MCCB17的保护。我们还将在Shewanella藻类和颤音中构建本地同源物QNRA和QNR的缺失,这是各自的储层生物,并测试奎诺酮易感性和在与其天然栖息地相关的环境条件下的敏感性和生长差异。我们还将构建QNRS-LACZ转录融合,以筛选大肠杆菌转座子突变库文库,以获取环氧霉素对QNR诱导所必需的基因。在特定目标3下,我们建议通过测试QNR对本机生物体中的QNR对其他大肠杆菌基因表达的影响,以评估QNR与其他蛋白质的相互作用。
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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David C Hooper其他文献
David C Hooper的其他文献
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{{ truncateString('David C Hooper', 18)}}的其他基金
Subproject 4 Antimicrobials and Efflux Pumps in Staphylococcus aureus Infection
子项目 4 金黄色葡萄球菌感染中的抗菌药物和外排泵
- 批准号:
9151289 - 财政年份:2016
- 资助金额:
$ 41.13万 - 项目类别:
Antimicrobials and Efflux Pumps in Staphylococcus aureus Infection
金黄色葡萄球菌感染中的抗菌药物和外排泵
- 批准号:
8376876 - 财政年份:2012
- 资助金额:
$ 41.13万 - 项目类别:
Antimicrobials and Efflux Pumps in Staphylococcus aureus Infection
金黄色葡萄球菌感染中的抗菌药物和外排泵
- 批准号:
8202963 - 财政年份:2011
- 资助金额:
$ 41.13万 - 项目类别:
Subproject 4: Role of Pumps in Resistance, Physiology, and Infection
子项目 4:泵在抵抗、生理和感染中的作用
- 批准号:
10571916 - 财政年份:2009
- 资助金额:
$ 41.13万 - 项目类别:
Subproject 4: Role of Pumps in Resistance, Physiology, and Infection
子项目 4:泵在抵抗、生理和感染中的作用
- 批准号:
10327905 - 财政年份:2009
- 资助金额:
$ 41.13万 - 项目类别:
Mechanism and Spread of Qnr-Mediated Resistance
Qnr介导的耐药机制和传播
- 批准号:
6705185 - 财政年份:2004
- 资助金额:
$ 41.13万 - 项目类别:
Mechanism and Spread of Qnr-Mediated Resistance
Qnr介导的耐药机制和传播
- 批准号:
6835177 - 财政年份:2004
- 资助金额:
$ 41.13万 - 项目类别:
Mechanism and Spread of Qnr-Mediated Resistance
Qnr介导的耐药机制和传播
- 批准号:
7334159 - 财政年份:2004
- 资助金额:
$ 41.13万 - 项目类别:
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