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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：
10203804
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/10203804
关键词：
Address Anti-Bacterial Agents Antibiotics Applications Grants Aspartate Aspartic Acid Attention Bacteria Binding 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 Lead Lytic Meropenem Methodology Methods Microbiology 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.

项目总结/文摘