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Small molecule inhibitors of lytic transglycosylase to potentiate beta-lactam antibiotics

裂解性转糖基酶小分子抑制剂可增强 β-内酰胺抗生素的作用

基本信息

批准号：
10078254
负责人：
FOCCO VAN DEN AKKER
金额：
$ 21.01万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
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：
2020-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10078254
关键词：
Acinetobacter baumannii Active Sites Anabolism Animals Anti-Bacterial Agents Antibiotics Antimicrobial Resistance Bacteria Bacterial Antibiotic Resistance Bacterial Proteins Binding Biological Biological Assay Campylobacter jejuni Carbohydrates Cell Death Cell Wall Cells Chemicals Chemosensitization Crystallography Cytolysis Cytoplasm Disaccharides Docking Drug Targeting Enterobacter cloacae Enzyme Inhibitor Drugs Enzymes Escherichia coli Glucosamine Helicobacter pylori Klebsiella aerogenes Knock-out Label Libraries Link Lytic Mechanics Microbiology Monobactams Multiple Bacterial Drug Resistance Natural Products Neisseria Neisseria gonorrhoeae Penicillin-Binding Proteins Peptidoglycan Pharmaceutical Chemistry Proteins Pseudomonas aeruginosa Pyrrolidines Resistance Shapes Structure Testing bacterial resistance base beta-Lactamase beta-Lactams biophysical techniques crosslink design global health glycosyltransferase improved in silico inhibitor/antagonist novel novel therapeutics pathogen pathogenic bacteria protein crosslink resistance mechanism scaffold screening small molecule inhibitor tool

项目摘要

The rapid emergence of antibiotic-resistant bacteria is a major global health threat. This spurs the need to revisit key antibacterial drug targets such as the peptidoglycan (PG) layer. The PG synthesis machinery is targeted by β-lactam antibiotics that inhibit penicillin-binding proteins (PBP) which crosslink PG strands. A main resistance mechanism is the expression of β-lactamases that can degrade β-lactams. There is thus a critical need for new antibiotics or for avenues to re-sensitize bacteria to β-lactam antibiotics. For the latter, one approach is developing β-lactamase inhibitors; unfortunately, the 5 current inhibitors do not inhibit certain key β-lactamases, and there are resistance mechanisms via inhibitor-resistant β-lactamases. A second approach is to inhibit PG degrading lytic transglycosylases (LT), the focus of this application. Inhibition of LTs or knocking out LTs genetically has been shown to restore the efficacy of β-lactam antibiotics in many serious pathogens including Escherichia coli, Neisseria meningitides, Pseudomonas aeruginosa, Enterobacter aerogenes, Acinetobacter baumannii, Helicobacter pylori, and Campylobacter jejuni. This β-lactam potentiation involves two possible mechanisms of which, depending on the pathogen, either or both contribute. In the first mechanism, the inhibition of both PBP and LT leads to long non-cross-linked PG strands that cause cell wall bulges, weakening the cell wall. In the second mechanism, LT activity generates disaccharide PG product that, when recycled to the cytoplasm, increases β-lactamase expression in certain pathogens. Despite these compelling observations, there is only one promising LT inhibitor known, bulgecin A; however, this natural product carbohydrate-based inhibitor is very challenging for medicinal chemistry efforts. As a result, bulgecin A has not been very amenable to advancing inhibition studies towards animal studies and beyond. This application proposes to overcome this key roadblock by developing new LT inhibitors with scaffold(s) different from bulgecin A via biased (Aim 1) and non-biased fragment-based approaches (Aim 2). Aim 1: To identify new inhibitor fragments that retain bulgecin A's key N-acetyl group. N-acetyl containing compounds will be selected or designed aided by docking; their LT binding and inhibition will be probed by biophysical techniques, protein crystallography, and enzymatic assays. Compounds will be tested against multiple LTs known to bind bulgecin A, and which are amenable to crystallography (E. coli, P. aeruginosa, and C. jejuni) in order to identify at least one fragment binding to one LT as a novel starting point for optimization. Aim 2: To identify non-acetyl containing fragments that bind to the active site of LT, we will screen non- biased fragments against LTs for binding and inhibition as in Aim 1. Such fragments could bind to the N-acetyl binding pocket or to the adjacent pockets. Compounds will be obtained from an sp3 fragment library and from in silico screening of larger libraries. Hits from Aims 1 and 2 will be modified/grown/linked to improve binding and inhibition of one or more of the LTs and also tested microbiologically for the potentiation of β-lactam antibiotics.

抗生素耐药细菌的迅速出现是一个重大的全球健康威胁。这刺激了重新审视的需要

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Turnover Chemistry and Structural Characterization of the Cj0843c Lytic Transglycosylase of Campylobacter jejuni.

DOI：
10.1021/acs.biochem.1c00027
发表时间：
2021-04-13
期刊：
BIOCHEMISTRY
影响因子：
2.9
作者：
Kumar, Vijay;Mathure, Snigdha A.;Lee, Mijoon;Boorman, Jacob;Zeng, Ximin;Lin, Jun;Hesek, Dusan;Lastochkin, Elena;Mobashery, Shahriar;van den Akker, Focco
通讯作者：
van den Akker, Focco

Exploring the inhibition of the soluble lytic transglycosylase Cj0843c of Campylobacter jejuni via targeting different sites with different scaffolds.