Structure and Inhibition of the Conjugative DNA Relaxase-Helicase
Structure and Inhibition of the Conjugative DNA Relaxase-Helicase
批准号:
8274770
负责人:
Matthew R Redinbo
金额:
$35.55万
依托单位国家:
美国
项目类别:
财政年份:
2008
资助国家:
美国
项目状态:
已结题
起止时间:
2008-06-01 至 2014-05-31
关键词:
AmericanAntibiotic ResistanceBacteriaBacterial InfectionsBiological AssayBiologyC-terminalC-terminal binding proteinCatalytic DomainCell SurvivalCellsChemicalsClinicalColon CarcinomaComplexDNADNA relaxaseDevelopmentEnzymesEscherichia coliF FactorFertilityGenesGenetic ConjugationGoalsHealthHeartHospitalsHumanIn VitroInfectionMalignant neoplasm of ovaryMalignant neoplasm of prostateMediatingMethodsMicrobeMolecularMovementN-terminalNosocomial InfectionsNucleoproteinsOsteoporosisPharmaceutical PreparationsPhosphotyrosinePlasmidsPlayPopulationPrevalenceProcessProtein Binding DomainProteinsResistanceRoleRouteSalmonellaSiteStructureSystemTestingbacterial resistancebasedesignhelicaseinhibitor/antagonistinsightkillingsmalignant breast neoplasmmortalitynovelplasmid DNApreventpurgeresistant strainsmall moleculetool
中文摘要
项目概要
每年死于抗生素耐药性细菌感染的美国人比结肠、前列腺和卵巢感染还要多
癌症合并。接合 DNA 转移产生了大多数抗生素抗性细菌菌株,
感染人类。我们最近表明,对于 DNA 转移过程至关重要的松弛酶可以
使用各种小分子(包括一些骨质疏松症药物)可抑制纳摩尔级的疗效。
松弛酶抑制可防止 DNA 转移并选择性杀死抗生素抗性细菌。的松弛酶
接合 F 质粒是大型多功能 TraI 蛋白的一部分,该蛋白还含有高效解旋酶
和推定的蛋白质结合 C 端结构域。 TraI 的松弛酶、解旋酶和 C 端区域均是
对于接合 DNA 转移至关重要。该提案的重点是扩展我们的初步结构和
化学生物学研究的目标是了解 DNA 转移和开发的分子基础
能够杀死抗生素耐药细菌的小分子。该项目将实现四个具体目标:
1. 阐明一系列松弛酶抑制剂复合物的晶体结构。
2. 发现和合成新的松弛酶抑制剂并测试它们对结合和细菌存活的影响。
3. 揭示 TraI C 端结构域在接合转移中的作用。
4. 检查TraI接合解旋酶区域的结构、功能和抑制。
这些研究的结果将为第一批 DNA 之一提供详细的机制见解。
发现了操纵系统。此外,由于保守的松弛酶存在于一系列
病原微生物,我们的结果可能提供一种针对最危险的传染性细菌的新方法
那些对抗生素具有抗药性并能够将其抗药性传播到邻近细胞的细胞。项目叙述
接合DNA转移,抗生素抗性基因传播的主要途径
细菌群体是由 DNA 松弛酶和解旋酶启动和驱动的。我们最近展示了
可以以纳摩尔级的功效抑制接合松弛酶,并且这种抑制作用可以阻止 DNA
结合并选择性杀死抗生素抗性细菌。该项目将扩展我们的初步结构
和化学生物学发现,旨在了解 DNA 转移的分子基础
开发有效杀死抗生素耐药细菌的药物。
英文摘要
PROJECT SUMMARY
Antibiotic resistant bacterial infections kill more Americans each year than colon, prostate and ovarian
cancer combined. Conjugative DNA transfer generates most of the antibiotic resistant strains of bacteria that
infect humans. We have recently shown that the relaxase enzyme essential to this DNA transfer process can
be inhibited with nanomolar efficacy using a variety of small molecules, including some osteoporosis drugs.
Relaxase inhibition prevents DNA transfer and selectively kills antibiotic resistant bacteria. The relaxase of the
conjugative F plasmid is part of the large multifunctional TraI protein that also contains highly efficient helicase
and putative protein-binding C-terminal domains. The relaxase, helicase and C-terminal regions of TraI are all
essential for conjugative DNA transfer. This proposal focuses on extending our preliminary structural and
chemical biology studies with the goals of understanding the molecular basis of DNA transfer and developing
small molecules capable of killing antibiotic resistant bacteria. This project will accomplish four specific aims:
1. Elucidate crystal structures of a range of relaxase-inhibitor complexes.
2. Discover and synthesize new relaxase inhibitors and test their impact on conjugation and bacterial survival.
3. Unravel the role the TraI C-terminal domain plays in conjugative transfer.
4. Examine the structure, function and inhibition of the TraI conjugative helicase region.
Results from these studies will provide detailed mechanistic insights into one of the first DNA
manipulation systems discovered. In addition, because conserved relaxases are present in a range of
pathogenic microbes, our results may provide a novel method to target the most dangerous infectious bacteria
those that are antibiotic resistant and are capable of spreading their resistance to neighboring cells. PROJECT NARRATIVE
Conjugative DNA transfer, the primary route by which antibiotic resistance genes spread through
bacterial populations, is initiated and driven by DNA relaxase and helicase enzymes. We have recently shown
that conjugative relaxases can be inhibited with nanomolar efficacy, and that this inhibition prevents DNA
conjugation and selectively kills antibiotic resistant bacteria. This project will extend our preliminary structural
and chemical biology discoveries with the goal of understanding the molecular basis of DNA transfer and
developing drugs that potently kill antibiotic resistant bacteria.
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DOI:
10.1016/j.jmb.2008.12.057
发表时间:
2009-02-20
期刊:
JOURNAL OF MOLECULAR BIOLOGY
影响因子:
5.6
作者:
[Guogas, Laura M., Kennedy, Sarah A., Lee, Jin-Hyup, Redinbo, Matthew R.]
通讯作者:
Redinbo, Matthew R.
DOI:
10.1371/journal.pone.0029629
发表时间:
2011
期刊:
PloS one
影响因子:
3.7
作者:
[Johnson MD, Garrett CK, Bond JE, Coggan KA, Wolfgang MC, Redinbo MR]
通讯作者:
Redinbo MR
Turnover-dependent covalent inactivation of Staphylococcus aureus coenzyme A-disulfide reductase by coenzyme A-mimetics: mechanistic and structural insights.
辅酶 A-模拟物对金黄色葡萄球菌辅酶 A-二硫键还原酶的周转依赖性共价失活:机制和结构见解。
DOI:
10.1021/bi301026c
发表时间:
2012
期刊:
Biochemistry
影响因子:
2.9
作者:
[Wallace,BretD, Edwards,JonathanS, Wallen,JamieR, Moolman,WesselJA, vanderWesthuyzen,Renier, Strauss,Erick, Redinbo,MatthewR, Claiborne,Al]
通讯作者:
Claiborne,Al
Crystal structure of the plant epigenetic protein arginine methyltransferase 10.
植物表观遗传蛋白精氨酸转移酶10的晶体结构10。
DOI:
10.1016/j.jmb.2011.09.040
发表时间:
2011-11-18
期刊:
JOURNAL OF MOLECULAR BIOLOGY
影响因子:
5.6
作者:
[Cheng, Yuan, Frazier, Monica, Lu, Falong, Cao, Xiaofeng, Redinbo, Matthew R.]
通讯作者:
Redinbo, Matthew R.
Processing of Nonconjugative Resistance Plasmids by Conjugation Nicking Enzyme of Staphylococci.
用葡萄球菌的接合切口酶加工非接合抗性质粒。
DOI:
10.1128/jb.00832-15
发表时间:
2016
期刊:
Journal of bacteriology
影响因子:
3.2
作者:
[Pollet,RebeccaM, Ingle,JamesD, Hymes,JeffP, Eakes,ThomasC, Eto,KarinaYui, Kwong,StephenM, Ramsay,JoshuaP, Firth,Neville, Redinbo,MatthewR]
通讯作者:
Redinbo,MatthewR
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批准号:7721988
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Structure and Inhibition of the Conjugative DNA Relaxase-Helicase
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Structure and Inhibition of the Conjugative DNA Relaxase-Helicase
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Structure and Inhibition of the Conjugative DNA Relaxase-Helicase
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Structure and Inhibition of the Conjugative DNA Relaxase-Helicase
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