Determining the mechanism of inhibition of metallo-b-lactamase inhibitors
确定金属-b-内酰胺酶抑制剂的抑制机制
基本信息
- 批准号:9812399
- 负责人:
- 金额:$ 43.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAddressAnti-Bacterial AgentsAntibiotic ResistanceAntibioticsAntimicrobial ResistanceBacterial Antibiotic ResistanceBacterial InfectionsBindingBinding SitesBiochemicalCalorimetryCarbapenemsClinicalClinical TrialsCobaltComplexDataDevelopmentDialysis procedureElectron Spin Resonance SpectroscopyElectronsEnterobacteriaceaeEnzymatic BiochemistryEnzyme Inhibitor DrugsEnzyme KineticsEnzymesEquilibriumEvolutionFutureGenesGleanGoalsIonsKineticsKnowledgeMass Spectrum AnalysisMeasuresMediatingMetal Ion BindingMetalsMolecular ConformationNMR SpectroscopyOnline SystemsOrganismPathway interactionsPeer ReviewPlasmidsProteinsPublicationsPublishingRecombinantsReportingResearchResearch PersonnelResistanceResortSpectrum AnalysisStructureStructure-Activity RelationshipStudentsSystemTechniquesTherapeuticTimeTitrationsToxic effectTrainingUnited States National Institutes of HealthWorkZincanalogbacterial resistancebasebeta-Lactamasebeta-Lactamscandidate selectionclinical applicationclinical candidateclinical developmentclinically relevantexperimental studyfunctional groupglobal healthinhibitor/antagonistinterdisciplinary approachmeetingsmetalloenzymenoveloverexpressionpathogenic bacteriaprogramsscaffoldspectroscopic surveystoichiometryundergraduate studentweb site
项目摘要
PROJECT SUMMARY/ABSTRACT
Metallo-b-lactamases (MBLs) are bacterial enzymes that render pathogenic bacteria resistant to the largest class
of antibiotics. Although a number of MBL inhibitors have been published, clear structure-activity relationships
(SARs) are often difficult to discern, and none of these inhibitors has advanced to clinical use. We propose that
the disconnect between the discovery of inhibitors and the development of clinically-useful compounds is due,
in part, to a lack of understanding the mechanisms whereby these compounds work, and by the predominance
of metal-stripping mechanisms, which are inherently non-specific and have associated toxicity issues. To directly
address these issues, we propose to discern the mechanism of inhibition of several under-defined MBL inhibitors.
Specific aim #1 will characterize inhibition mechanisms of several MBL inhibitor classes. Many reported MBL
inhibitors contain functional groups with potential to bind metal ions, but their mechanisms remain undefined.
Here, we use a multidisciplinary approach to determine if selected classes of MBL inhibitors work by metal-
stripping, by ternary complex formation (inhibitor:metal ion:protein) or by other mechanisms. This information
will enable more effective SAR studies and allow better selection of candidates more suitable for clinical
applications.
Specific aim #2 will develop two novel techniques to probe inhibitor binding to MBLs. One technique is EPR-
based and is predicted to yield information about an invariant b-hairpin loop that resides over the MBL active
sites. The second technique is native MS-based and is predicted to yield direct information about the mechanism
of inhibition using lower concentrations of enzyme/inhibitor.
The long-term goal of this research program is to identify the most promising scaffolds for MBL inhibitors, which
can be given in combination with existing b-lactam containing antibiotics to treat antibiotic resistant bacterial
infections. Through clearly determining the mechanism of action of promising MBL inhibitor scaffolds, we will
provide a clearer pathway for these inhibitors to proceed to clinical trials.
项目总结/摘要
金属-β-内酰胺酶(MBL)是使病原菌对最大类抗生素耐药的细菌酶。
抗生素。虽然已经发表了许多MBL抑制剂,但明确的结构-活性关系
(SAR)通常难以辨别,这些抑制剂都没有进入临床使用。我们建议
抑制剂的发现和临床上有用的化合物的开发之间的脱节是由于,
部分原因是对这些化合物的作用机制缺乏了解,
的金属剥离机制,这是固有的非特异性,并有相关的毒性问题。直接
为了解决这些问题,我们建议辨别几种定义不足的MBL抑制剂的抑制机制。
具体目标#1将表征几种MBL抑制剂类别的抑制机制。许多人报告MBL
抑制剂含有具有结合金属离子潜力的官能团,但它们的机理仍不清楚。
在这里,我们使用多学科的方法来确定是否选择类MBL抑制剂的工作,通过金属-
通过三元复合物形成(抑制剂:金属离子:蛋白质)或通过其它机制进行剥离。这些信息
将实现更有效的SAR研究,并允许更好地选择更适合临床的候选人
应用.
具体目标#2将开发两种新技术来探测抑制剂与MBL的结合。一种技术是EPR-
基于并预测产生关于位于MBL活性区上的不变b-发夹环的信息。
网站.第二种技术是基于原生MS的,预计将产生有关机制的直接信息
使用较低浓度的酶/抑制剂进行抑制。
这项研究计划的长期目标是确定最有前途的MBL抑制剂支架,
可以与现有的含有β-内酰胺的抗生素联合给药,
感染.通过明确有前途的MBL抑制剂支架的作用机制,我们将
为这些抑制剂进入临床试验提供了更清晰的途径。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
MICHAEL W CROWDER其他文献
MICHAEL W CROWDER的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('MICHAEL W CROWDER', 18)}}的其他基金
Machine Learning Approach for finding novel metallo-b-lactamase inhibitors
寻找新型金属 β 内酰胺酶抑制剂的机器学习方法
- 批准号:
10514544 - 财政年份:2019
- 资助金额:
$ 43.35万 - 项目类别:
Time-dependent structural studies on dinuclear metal ion containing enzymes
含双核金属离子酶的时间依赖性结构研究
- 批准号:
7940321 - 财政年份:2010
- 资助金额:
$ 43.35万 - 项目类别:
METALLO BETA LACTAMASE FROM X MALTOPHILIA
来自 X Maltophilia 的 METALLO β 内酰胺酶
- 批准号:
6124376 - 财政年份:1997
- 资助金额:
$ 43.35万 - 项目类别:
METALLO BETA LACTAMASE FROM X MALTOPHILIA
来自 X Maltophilia 的 METALLO β 内酰胺酶
- 批准号:
2469460 - 财政年份:1997
- 资助金额:
$ 43.35万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 43.35万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 43.35万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 43.35万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 43.35万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 43.35万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 43.35万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 43.35万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 43.35万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 43.35万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 43.35万 - 项目类别:
Research Grant