Bulgecin Template for Potentiation of beta-Lactam Antibiotics
用于增强 β-内酰胺抗生素的 Bulgecin 模板
基本信息
- 批准号:10040793
- 负责人:
- 金额:$ 50.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAnti-Bacterial AgentsAntibioticsApplications GrantsAspartateAspartic AcidAttentionBacteriaBindingCeftazidimeChemosensitizationClinicalComplexComputer AnalysisCytolysisEventExhibitsFailureFluorescence MicroscopyGene ClusterGenesGram-Negative BacteriaGram-Negative Bacterial InfectionsHost resistanceIn VitroInfectionLeadLyticMeropenemMethodologyMethodsMicrobiologyMonobactamsNatural ProductsOrganismPathway interactionsPenetrationPhasePreparationProcessProductionPropertyPseudomonas aeruginosaPseudomonas aeruginosa infectionReactionReportingResearchResistanceRodent ModelRoentgen RaysScanning Electron MicroscopySeriesSerineSiteStructureWorkanalogbactericidebeta-Lactamschemical synthesisexperimental studyfightinghuman pathogenin vivolead optimizationnovelnovel strategiespathogenperiplasmresistance mechanism
项目摘要
Project Summary/Abstract
Gram-negative bacteria have become broadly resistant to known classes of antibiotics. Treatment of infections
by these pathogens has become increasingly challenging and efforts in the past two decades in discoveries of
new classes of antibacterial agents have failed. In this grant application, we have turned our attention to
bulgecins, a group of three natural products (bulgecins A, B and C) discovered in the 1980s, which potentiate
the activities of b-lactam antibiotics to Gram-negative bacteria. The three natural products were prepared by
total synthesis and we documented the potentiation activity in microbiological experiments. Furthermore, we
documented by both fluorescence microscopy and by scanning-electron microscopy that the combination of
bulgecin A and a b-lactam antibiotic (ceftazidime or meropenem) cause bulges in the bacterial envelope, which
are points of structural instability that burst and lead to bactericidal effect. In addition, we documented that
merely two lytic transglycosylases out of 11 in Pseudomonas aeruginosa—Slt and MltD (with ceftazidime) and
Slt and MltG (with meropenem)—are the targets of bulgecin A. We also report the X-ray structure for the
complex of Slt with bulgecin A. We disclose the next phase of this research in two Specific Aims. Specific Aim
1 addresses our planned analysis of the bulgecin-biosynthetic cluster, which we discovered recently. The
eight-gene cluster converts L-serine and L-aspartic acid to bulgecinine, a key structural component of
bulgecins, and then in turn, to bulgecins A, B and C. We propose to study these genes both for their
enzymological reactions and for their structures. A proposal is outlined to prepare the high-value bulgecinine
using a host bacterium as a “one-pot” reaction vessel. We already have reported a chemical synthesis for
bulgecinine and a second (shorter) synthetic approach is also proposed. A detailed plan is outlined in Specific
Aim 2 to optimize the bulgecin template. The process takes advantage of our X-ray structure for the complex of
Slt and bulgecin A in a computational analysis to identify analogs that will bind more potently to lytic
transglycosynases and achieve penetration into Gram-negatives more avidly. The proposed targets will be
synthesized and fully analyzed in a series of both in vitro and in vivo experiments in identification of a suitable
combination of a bulgecin analog with a b-lactam antibiotic in fighting Gram-negative bacterial infections.
项目总结/摘要
革兰氏阴性菌已经对已知种类的抗生素产生了广泛的耐药性。治疗感染
在过去的二十年里,
新型抗菌剂已经失败。在这份拨款申请中,我们将注意力转向了
bulgecins是在20世纪80年代发现的一组三种天然产物(bulgecins A、B和C),其增强
β-内酰胺类抗生素对革兰阴性菌的抗菌活性。这三种天然产物通过以下步骤制备:
全合成,我们在微生物实验中记录了增强活性。而且我们
通过荧光显微镜和扫描电子显微镜记录,
bulgecin A和b-内酰胺抗生素(头孢他啶或美罗培南)引起细菌包膜的隆起,
是结构不稳定的点,破裂并导致杀菌作用。此外,我们还记录了
铜绿假单胞菌中11种酶中仅有两种溶解性转糖基酶-Slt和MltD(头孢他啶),
Slt和MltG(与美罗培南)-是bulgecin A的靶点。我们还报告了X射线结构的
Slt与bulgecin A的复合物。我们在两个具体目标中披露了这项研究的下一阶段。具体目标
1解决了我们计划的bulgecin生物合成集群,我们最近发现的分析。的
八个基因簇将L-丝氨酸和L-天冬氨酸转化为bulgecinine,bulgecinine是一种关键的结构成分,
bulgecins,然后依次转化为bulgecins A、B和C。我们建议研究这些基因,
酶反应及其结构。本文提出了制备高价值的Bulgecinine的建议
使用宿主细菌作为“一锅法”反应容器。我们已经报道了一种化学合成方法,
bulgecinine和第二个(较短)的合成方法也提出了。详细的计划概述在具体
目的2优化bulgecin模板。该过程利用了我们的X射线结构的复杂性,
Slt和bulgecin A进行计算分析,以鉴定将更有效地结合裂解的类似物。
转糖苷酶和实现渗透到革兰氏阴性菌更贪婪。拟议的目标将是
合成并在一系列体外和体内实验中充分分析,以鉴定合适的
bulgecin类似物与b-内酰胺抗生素的组合在对抗革兰氏阴性细菌感染中的应用。
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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Shahriar Mobashery其他文献
Shahriar Mobashery的其他文献
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{{ truncateString('Shahriar Mobashery', 18)}}的其他基金
Bulgecin Template for Potentiation of beta-Lactam Antibiotics
用于增强 β-内酰胺抗生素的 Bulgecin 模板
- 批准号:
10203804 - 财政年份:2020
- 资助金额:
$ 50.2万 - 项目类别:
Bulgecin Template for Potentiation of beta-Lactam Antibiotics
用于增强 β-内酰胺抗生素的 Bulgecin 模板
- 批准号:
10631928 - 财政年份:2020
- 资助金额:
$ 50.2万 - 项目类别:
Bulgecin Template for Potentiation of beta-Lactam Antibiotics
用于增强 β-内酰胺抗生素的 Bulgecin 模板
- 批准号:
10438764 - 财政年份:2020
- 资助金额:
$ 50.2万 - 项目类别:
Cell-Wall Recycling and Nexus to Antibiotic Resistance
细胞壁回收及其与抗生素耐药性的关系
- 批准号:
10401291 - 财政年份:2019
- 资助金额:
$ 50.2万 - 项目类别:
Cell-Wall Recycling and Nexus to Antibiotic Resistance
细胞壁回收及其与抗生素耐药性的关系
- 批准号:
10627796 - 财政年份:2019
- 资助金额:
$ 50.2万 - 项目类别:
Cell-Wall Recycling and Nexus to Antibiotic Resistance
细胞壁回收及其与抗生素耐药性的关系
- 批准号:
9920167 - 财政年份:2019
- 资助金额:
$ 50.2万 - 项目类别:
Inducible Antibiotic Resistance in Methicillin-Resistant Staphylococcus Aureus
耐甲氧西林金黄色葡萄球菌诱导的抗生素耐药性
- 批准号:
8600959 - 财政年份:2013
- 资助金额:
$ 50.2万 - 项目类别:
Inducible Antibiotic Resistance in Methicillin-Resistant Staphylococcus aureus
耐甲氧西林金黄色葡萄球菌诱导的抗生素耐药性
- 批准号:
10083692 - 财政年份:2013
- 资助金额:
$ 50.2万 - 项目类别:
Beta-Lactam Resistance Mechanisms of Staphylococcus aureus
金黄色葡萄球菌的β-内酰胺耐药机制
- 批准号:
10586370 - 财政年份:2013
- 资助金额:
$ 50.2万 - 项目类别:
Inducible Antibiotic Resistance in Methicillin-Resistant Staphylococcus Aureus
耐甲氧西林金黄色葡萄球菌诱导的抗生素耐药性
- 批准号:
8479497 - 财政年份:2013
- 资助金额:
$ 50.2万 - 项目类别:
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