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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：
10631928
负责人：
Shahriar Mobashery
金额：
$ 62.9万
依托单位：
UNIVERSITY OF NOTRE DAME
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：
https://reporter.nih.gov/project-details/10631928
关键词：
Address Anti-Bacterial Agents Antibiotics Applications Grants Aspartate Aspartic Acid Attention Bacteria Binding Biological Ceftazidime Chemosensitization Clinical Complex Computer Analysis Cytolysis Event Exhibits Failure Fluorescence Microscopy Gene Cluster Genes Gram-Negative Bacteria Gram-Negative Bacterial Infections Host resistance In Vitro Infection Lytic Meropenem Methodology Methods Monobactams Natural Products Organism Pathway interactions Penetration Phase Preparation Process Production Property Pseudomonas aeruginosa Pseudomonas aeruginosa infection Reaction Reporting Research Resistance Rodent Model Roentgen Rays Scanning Electron Microscopy Series Serine Site Structure Work analog bactericide beta-Lactams chemical synthesis experimental study fighting human pathogen in vivo lead optimization novel novel strategies pathogen periplasm resistance 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.

项目摘要/摘要革兰氏阴性细菌已经对已知类别的抗生素产生了广泛的抗药性。感染的治疗这些病原体已经变得越来越具有挑战性，在过去的二十年里，在发现新的抗菌剂已经失败了。在这项拨款申请中，我们将注意力转向 Bulgecins是20世纪80年代发现的一组三种天然产物(Bulgecins A，B和C)，它们能增强 β-内酰胺类抗生素对革兰氏阴性菌的抗菌活性。这三种天然产物是由全合成，并在微生物学实验中记录了其增强活性。此外，我们荧光显微镜和扫描电子显微镜都证明了 Bulgecin A和一种b-内酰胺类抗生素(头孢他啶或美罗培南)会导致细菌包膜肿胀，这是是结构不稳定性的点，会破裂并导致杀菌效果。此外，我们还记录了在铜绿假单胞菌-SLT和MltD(使用头孢他啶)中，仅有11种中的两种裂解糖基酶和 SLT和MltG(与美罗培南)-是Bulgecin A的靶点。我们还报道了该药物的X射线结构。 SLT与Bulgecin A的复合体。我们在两个具体目标上披露了这项研究的下一阶段。特定目标 1解决了我们最近发现的对Bulgecin-生物合成簇的计划分析。这个八个基因簇将L-丝氨酸和L-天冬氨酸转化为灯盏花碱，这是我们建议对这些基因进行研究，研究它们的酶反应和它们的结构。提出了制备高附加值白花蛇舌碱的建议用宿主菌作为“一锅”反应容器。我们已经报道了一种化学合成还提出了第二种(较短的)合成方法。一项详细的计划在具体的目的优化白花蛇舌菌素模板。这一过程利用了我们的X射线结构来获得复合体 SLT和Bulgecin A在计算分析中的应用，以确定将更有效地与Lytic结合的类似物转糖合成酶，并实现更积极地渗透到革兰氏阴性菌。拟议的目标将是在一系列体外和体内实验中合成和充分分析了一种合适的灯盏花素类似物与β-内酰胺类抗生素联合治疗革兰氏阴性细菌感染。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Penetration through Outer Membrane and Efflux Potential in Pseudomonas aeruginosa of Bulgecin A as an Adjuvant to β-Lactam Antibiotics.

DOI：
10.3390/antibiotics12020358
发表时间：
2023-02-09
期刊：
ANTIBIOTICS-BASEL
影响因子：
4.8
作者：
Kim, Choon;Tomoshige, Shusuke;Lee, Mijoon;Zgurskaya, Helen I.;Mobashery, Shahriar
通讯作者：
Mobashery, Shahriar

Unconventional Antibacterials and Adjuvants.