Targeting NuoD for the treatment of H. pylori
靶向 NuoD 治疗幽门螺杆菌
基本信息
- 批准号:10659783
- 负责人:
- 金额:$ 86.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-01 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:AmoxicillinAnti-Bacterial AgentsAntibioticsAttentionBacteriaBindingBinding ProteinsBiochemicalBiological AssayBiological AvailabilityCarcinogensCategoriesCell Membrane PermeabilityCellsChemistryChronicClarithromycinCollectionComplexDatabasesDevelopmentDrug KineticsDrug resistanceEpithelial CellsFeedbackGalactoseGenus HippocampusGlucoseGoalsGrowthHelicobacterHelicobacter InfectionsHelicobacter pyloriHepatocyteHomology ModelingHumanInflammationLigandsLiquid substanceMalignant NeoplasmsMeasuresMetronidazoleMicrosomesMitochondriaModelingMonitorNADH dehydrogenase (ubiquinone)OralOxygen ConsumptionPeptic UlcerPharyngeal structurePhosphotransferasesPropertyProton Pump InhibitorsReportingResistanceResistance developmentRespirationSeriesSolubilityStomachStomach CarcinomaStress TestsStructureTestingUlcerantagonistchronic infectioncombatcounterscreencytotoxicitydesigndrug developmentdrug resistant pathogendruggable targetexperimental studygastrointestinalgut microbiotaimprovedin vitro Assayin vitro testingin vivoin vivo Modelinhibitorlead candidatelead optimizationmalignant stomach neoplasmmicrobiomemutantnovelnovel therapeuticspathogenpathogenic bacteriapharmacologicpre-clinicalpriority pathogenresistant strainscaffoldsynergismvirtualvirtual screening
项目摘要
This proposal aims to develop novel, more effective, and selective therapies for the treatment of Helicobacter
pylori infections. Chronic infection with H. pylori causes peptic ulcers and gastric cancer. H. pylori is an
important drug-resistant pathogen, which is categorized as a high-priority pathogen by the WHO. Standard
therapy consists of a proton pump inhibitor (PPI) and two broad-spectrum antibiotics, usually clarithromycin
with either metronidazole or amoxicillin. These combinations are becoming increasingly ineffective with high
resistance rates, and substantially disrupt the gut's healthy microbiome. There is a considerable unmet need
for novel, more effective, and selective antibiotics to eradicate H. pylori. In our preliminary studies, we identified
the NuoD interface of Complex I as a druggable target for H. pylori. Respiration through Complex I is essential
for H. pylori, but not for most other bacteria, offering mechanistic selectivity and minimizing disruption of the
microbiome. We developed and validated a virtual screening platform for this target to identify leads with
improved pharmacological properties using the initial inhibitors. The virtual screen identifed hits that are
synthetically tractable with demonstrated on-target antibacterial activity, and both ex vivo and in vivo efficacy
against H. pylori. The ultimate aim of the proposal is to obtain carefully validated, narrow spectrum, orally
bioavailable, and efficacious NuoD inhibitors that will form the basis of a subsequent preclinical antibiotic
development effort. These studies will also provide a deeper understanding of H. pylori respiration and the
development of selective antibiotics against H. pylori.
该提案旨在开发新的、更有效的、选择性的治疗螺杆菌的疗法
幽门感染H.慢性感染。幽门导致消化性溃疡和胃癌。H.幽门螺杆菌是一种
重要的耐药病原体,WHO将其归类为高优先级病原体。标准
治疗包括质子泵抑制剂(PPI)和两种广谱抗生素,通常是克拉霉素
甲硝唑或阿莫西林都可以这些组合越来越无效,
耐药率,并大大破坏肠道的健康微生物组。有相当多的需求没有得到满足
寻找新的、更有效的和选择性的抗生素来根除H.幽门螺杆菌。在我们的初步研究中,我们发现
复合物I的NuoD界面作为H.幽门。通过复合物I的反应是必不可少的
螺杆幽门螺杆菌,但不是大多数其他细菌,提供机械选择性和最大限度地减少破坏的
微生物组我们为此目标开发并验证了一个虚拟筛选平台,
使用初始抑制剂改善了药理学性质。虚拟屏幕识别的命中,
合成上易处理,具有已证实的靶向抗菌活性,以及离体和体内功效
螺旋杆菌幽门螺杆菌。该提案的最终目的是获得经过仔细验证的、窄谱的、口头的
生物可利用和有效的NuoD抑制剂,将形成后续临床前抗生素的基础
发展努力。这些研究也将提供对H.幽门呼吸和
抗H.幽门螺杆菌。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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Michael LaFleur其他文献
Michael LaFleur的其他文献
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{{ truncateString('Michael LaFleur', 18)}}的其他基金
Development of a Dual-Targeting ClpP Activating Antibiotic
双靶点 ClpP 激活抗生素的开发
- 批准号:
10760586 - 财政年份:2023
- 资助金额:
$ 86.55万 - 项目类别:
A New Approach to Treat Prosthetic Joint Infections with a ClpP Activating Antibiotic
使用 ClpP 激活抗生素治疗假体关节感染的新方法
- 批准号:
10576404 - 财政年份:2021
- 资助金额:
$ 86.55万 - 项目类别:
A New Approach to Treat Prosthetic Joint Infections with a ClpP Activating Antibiotic
使用 ClpP 激活抗生素治疗假体关节感染的新方法
- 批准号:
10365956 - 财政年份:2021
- 资助金额:
$ 86.55万 - 项目类别:
Development of ureadepsipetides for drug-resistant infections
治疗耐药感染的脲肽肽的开发
- 批准号:
10525228 - 财政年份:2018
- 资助金额:
$ 86.55万 - 项目类别:
Development of ureadepsipetides for drug-resistant infections
治疗耐药感染的脲肽肽的开发
- 批准号:
10308010 - 财政年份:2018
- 资助金额:
$ 86.55万 - 项目类别:
Development of ureadepsipetides for drug-resistant infections
治疗耐药感染的脲肽肽的开发
- 批准号:
10063811 - 财政年份:2018
- 资助金额:
$ 86.55万 - 项目类别:
Bactericidal antibiotic for Vancomycin Resistant Enterococci
针对万古霉素耐药肠球菌的杀菌抗生素
- 批准号:
9243208 - 财政年份:2016
- 资助金额:
$ 86.55万 - 项目类别:
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