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:
- 金额:$ 21.01万
- 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:2020-01-01 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:Acinetobacter baumanniiActive SitesAnabolismAnimalsAnti-Bacterial AgentsAntibioticsAntimicrobial ResistanceBacteriaBacterial Antibiotic ResistanceBacterial ProteinsBindingBiologicalBiological AssayCampylobacter jejuniCarbohydratesCell DeathCell WallCellsChemicalsChemosensitizationCrystallographyCytolysisCytoplasmDisaccharidesDockingDrug TargetingEnterobacter cloacaeEnzyme Inhibitor DrugsEnzymesEscherichia coliGlucosamineHelicobacter pyloriKlebsiella aerogenesKnock-outLabelLibrariesLinkLyticMechanicsMicrobiologyMonobactamsMultiple Bacterial Drug ResistanceNatural ProductsNeisseriaNeisseria gonorrhoeaePenicillin-Binding ProteinsPeptidoglycanPharmaceutical ChemistryProteinsPseudomonas aeruginosaPyrrolidinesResistanceShapesStructureTestingbacterial resistancebasebeta-Lactamasebeta-Lactamsbiophysical techniquescrosslinkdesignglobal healthglycosyltransferaseimprovedin silicoinhibitor/antagonistnovelnovel therapeuticspathogenpathogenic bacteriaprotein crosslinkresistance mechanismscaffoldscreeningsmall molecule inhibitortool
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:
- 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.
- DOI:10.1002/pro.4683
- 发表时间:2023-07
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
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FOCCO VAN DEN AKKER其他文献
FOCCO VAN DEN AKKER的其他文献
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{{ truncateString('FOCCO VAN DEN AKKER', 18)}}的其他基金
Developing novel pyrazolidinone antibiotics targeting PBP3 to overcome resistance mechanisms
开发针对 PBP3 的新型吡唑烷酮抗生素以克服耐药机制
- 批准号:
10590839 - 财政年份:2023
- 资助金额:
$ 21.01万 - 项目类别:
Targeting Escherichia coli PBP1b using fragment-based approaches
使用基于片段的方法靶向大肠杆菌 PBP1b
- 批准号:
10374158 - 财政年份:2021
- 资助金额:
$ 21.01万 - 项目类别:
Targeting Escherichia coli PBP1b using fragment-based approaches
使用基于片段的方法靶向大肠杆菌 PBP1b
- 批准号:
10217694 - 财政年份:2021
- 资助金额:
$ 21.01万 - 项目类别:
CRYSTALLOGRAPHIC STUDIES OF ANTIBIOTIC RESISTANCE PROTEINS AND SIGNAL TRANSDUCTI
抗生素耐药蛋白和信号转导的晶体学研究
- 批准号:
8362188 - 财政年份:2011
- 资助金额:
$ 21.01万 - 项目类别:
CRYSTALLOGRAPHIC STUDIES OF ANTIBIOTIC RESISTANCE PROTEINS AND SIGNAL TRANSDUCTI
抗生素耐药蛋白和信号转导的晶体学研究
- 批准号:
8170149 - 财政年份:2010
- 资助金额:
$ 21.01万 - 项目类别:
CRYSTALLOGRAPHIC STUDIES OF ANTIBIOTIC RESISTANCE PROTEINS AND SIGNAL TRANSDUCTI
抗生素耐药蛋白和信号转导的晶体学研究
- 批准号:
7954491 - 财政年份:2009
- 资助金额:
$ 21.01万 - 项目类别:
CRYSTALLOGRAPHIC STUDIES OF ANTIBIOTIC RESISTANCE AND SIGNAL TRANSDUCTION
抗生素耐药性和信号转导的晶体学研究
- 批准号:
7726243 - 财政年份:2008
- 资助金额:
$ 21.01万 - 项目类别:
Mechanistic studies and inhibition strategies for antibiotic resistance
抗生素耐药性的机制研究和抑制策略
- 批准号:
7884373 - 财政年份:2007
- 资助金额:
$ 21.01万 - 项目类别:
Mechanistic studies and inhibition strategies for antibiotic resistance
抗生素耐药性的机制研究和抑制策略
- 批准号:
7658125 - 财政年份:2007
- 资助金额:
$ 21.01万 - 项目类别:
CRYSTALLOGRAPHIC STUDIES OF ANTIBIOTIC RESISTANCE AND SIGNAL TRANSDUCTION
抗生素耐药性和信号转导的晶体学研究
- 批准号:
7602310 - 财政年份:2007
- 资助金额:
$ 21.01万 - 项目类别:
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