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中文摘要
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项目总结 每年死于抗生素耐药性细菌感染的美国人比死于结肠癌、前列腺癌和卵巢癌的人数还多。 癌症加在一起。接合DNA转移产生了大多数耐抗生素的细菌菌株 感染人类。我们最近已经证明,DNA转移过程中必不可少的松弛酶可以 使用各种小分子药物,包括一些骨质疏松症药物,以纳米分子的功效抑制。 松弛酶抑制可防止DNA转移,并选择性地杀死抗药性细菌。松弛的心情 接合F质粒是大的多功能TraI蛋白的一部分,该蛋白也含有高效的解旋酶 以及推测的蛋白结合C末端结构域。TRAI的松弛酶、解旋酶和C末端区域都是 对于接合的DNA转移来说是必不可少的。这项提案的重点是延长我们初步的结构和 以了解DNA转移的分子基础和发展为目标的化学生物学研究 能够杀死抗药性细菌的小分子。该项目将实现四个具体目标: 1.阐明了一系列松弛酶抑制剂复合体的晶体结构。 2.发现和合成新的松弛酶抑制剂,并测试它们对接合和细菌存活的影响。 3.揭示Trai C-末端结构域在结合转移中的作用。 4.研究TRAI结合解旋酶区的结构、功能及其抑制作用。 这些研究的结果将提供对第一批DNA之一的详细机制洞察 发现了操控系统。此外,因为保守的松弛酶存在于一系列 致病微生物,我们的结果可能会提供一种新的方法来针对最危险的感染细菌 那些对抗生素有抗药性并能够将耐药性传播给邻近细胞的细胞。项目叙事 接合DNA转移,抗生素耐药基因传播的主要途径 细菌种群,是由DNA松弛酶和解旋酶启动和驱动的。我们最近展示了 结合松弛酶可以纳摩尔效应被抑制,并且这种抑制可以阻止DNA 结合并选择性地杀死抗药性细菌。这个项目将延长我们初步的结构 和化学生物学的发现,目的是了解DNA转移和 开发能有效杀死抗生素耐药性细菌的药物。
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.
期刊论文(5)
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会议论文
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.
Understanding and Controlling Drug Metabolism by the Gut Microbiota to Improve Human Health
Understanding and Controlling Drug Metabolism by the Gut Microbiota to Improve Human Health
Structural Basis for Hormone and Neurotransmitter Processing by Gut Microbial Enzymes
Structural Basis for Hormone and Neurotransmitter Processing by Gut Microbial Enzymes
海外基金