Potent Antifolates as New Therapeutics for MRSA
有效的抗叶酸剂作为 MRSA 的新疗法
基本信息
- 批准号:8089567
- 负责人:
- 金额:$ 76.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-08-01 至 2013-06-30
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAnimalsAnti-Bacterial AgentsAntibioticsAwardBacteriaBiologicalBiological AvailabilityCollaborationsComplexConnecticutCryptosporidiosisCryptosporidiumDevelopmentDihydrofolate ReductaseDoseDrug KineticsEnzyme Inhibitor DrugsEnzyme InhibitorsEnzymesEvaluationExhibitsFolic Acid AntagonistsGenerationsGenetic MaterialsGrantGrowthHalf-LifeHomologous GeneHumanIn VitroInfectionLeadLinkMethicillin ResistanceMontanaNatureNew AgentsOrganismParasitesPharmaceutical ChemistryPharmacologic SubstancePhasePhenotypePositioning AttributePropertyProtozoaReportingResearch PersonnelResistanceResolutionScienceSeriesSkin TissueSmall Business Technology Transfer ResearchSoft Tissue InfectionsStagingStaphylococcus aureusStreptococcus pyogenesStructureTherapeuticUniversitiesWorkanalogbasebiodefensechemotherapydesigndiaminopyrimidineefficacy evaluationfungusimprovedin vivoindexinginhibitor/antagonistlead seriesmeetingsnovelnovel therapeuticspathogenpublic health relevanceresearch studyresistant strainscaffold
项目摘要
DESCRIPTION (provided by applicant): This Phase II STTR proposal describes a collaborative effort between researchers in the Department of Pharmaceutical Sciences at the University of Connecticut and Promiliad Biopharma to develop efficacious antibiotics targeting both methicillin-resistant strains of Staphylococcus aureus (MRSA) and Streptococcus pyogenes. We have recently completed a Phase I STTR grant that was focused on developing agents against the parasitic protozoan Cryptosporidium hominis by targeting the essential enzyme dihydrofolate reductase (DHFR). Through this work we developed the most potent and selective inhibitors of this enzyme reported to date and showed efficacy against the cultured parasite. In parallel with these efforts targeting Cryptosporidium, we examined the generality of this compound class to inhibit DHFR from other pathogenic organisms and found that this scaffold can be customized to potently target a wide range of pathogenic DHFR enzymes, including that from MRSA and Streptococcus pyogenes. We intend to capitalize on the high-profile nature of these organisms by switching the focus of our first proof-of-concept antibiotic. We have shown that the compounds effectively inhibit the growth of various phenotypes of MRSA and Streptococcus pyogenes. Moreover, we have determined several high-resolution crystal structures of the pathogenic MRSA enzyme in complex with representative inhibitors, placing us in a strong position to further develop these new antibiotics. The efforts to develop an efficacious candidate compound will evolve through three specific aims. In the first Aim, we will complete an initial analog series and select two lead compounds to move forward into animal studies in the second specific aim. These studies will determine key pharmacokinetic parameters (bioavailability, half-life) for our compounds as well as determine efficacy in an animal model of infection. In the third specific aim, we will explore new, structure-based designs to enhance the selectivity of our compounds for the pathogenic forms of DHFR over the human homolog. Completion of these studies will position us to attract outside investors and partners to progress our compounds for an IND application.
PUBLIC HEALTH RELEVANCE: Despite decades of work on the discovery of antibiotics, the continued emergence of resistance organisms threatens to render many of our best antibiotics obsolete. We are working to develop new agents against that function as effective monotherapies against the methicillin-resistant strain of Staphylococcus aureus (MRSA) and Streptococcus pyogenes. Specifically we are targeting the essential enzyme dihydrofolate reductase (DHFR) that is required by the bacteria to synthesize key components needed to replicate its genetic material.
描述(由申请人提供):这项第二阶段STTR提案描述了康涅狄格大学药学系和Promiliad Biophma的研究人员合作开发针对耐甲氧西林金黄色葡萄球菌(MRSA)和化脓性链球菌的有效抗生素。我们最近完成了一项第一阶段的STTR拨款,重点是通过瞄准基本酶二氢叶酸还原酶(DHFR)来开发抗寄生虫原生动物人隐孢子虫的药物。通过这项工作,我们开发了迄今为止报道的最有效和最有选择性的该酶抑制剂,并显示出对培养的寄生虫的疗效。在这些针对隐孢子虫的努力的同时,我们检查了这类化合物抑制其他病原体DHFR的普遍性,发现这种支架可以被定制为有效地靶向广泛的致病DHFR酶,包括MRSA和化脓性链球菌的酶。我们打算通过改变我们第一个概念验证抗生素的重点来利用这些微生物的高调性质。我们已经证明,这些化合物有效地抑制了各种表型的MRSA和化脓性链球菌的生长。此外,我们还确定了致病MRSA酶与代表性抑制剂的复合体的几个高分辨晶体结构,使我们在进一步开发这些新抗生素方面处于有利地位。开发有效的候选化合物的努力将通过三个具体目标进行。在第一个目标中,我们将完成最初的模拟系列,并在第二个特定目标中选择两个先导化合物进行动物研究。这些研究将确定我们化合物的关键药代动力学参数(生物利用度、半衰期)以及在动物感染模型中的疗效。在第三个具体目标中,我们将探索新的、基于结构的设计,以提高我们的化合物对DHFR致病形式的选择性超过人类同系物。这些研究的完成将使我们能够吸引外部投资者和合作伙伴来推动我们的化合物申请IND。
与公共卫生相关:尽管几十年来一直致力于抗生素的发现,但耐药生物的持续出现可能会使我们许多最好的抗生素过时。我们正在努力开发新的药物来对抗这种作用,作为对抗耐甲氧西林金黄色葡萄球菌(MRSA)和化脓性链球菌的有效单一疗法。具体地说,我们的目标是二氢叶酸还原酶(DHFR),这是细菌合成复制其遗传物质所需的关键成分所需的。
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 }}
Dennis L. Wright其他文献
Dennis L. Wright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('Dennis L. Wright', 18)}}的其他基金
Therapeutic Agents Targeting Cryptococcal Infections
针对隐球菌感染的治疗药物
- 批准号:
10697960 - 财政年份:2023
- 资助金额:
$ 76.37万 - 项目类别:
New Agents for the Treatment on Mycobacteria Avium Infections
治疗鸟分枝杆菌感染的新药
- 批准号:
10597233 - 财政年份:2022
- 资助金额:
$ 76.37万 - 项目类别:
New Agents for the Treatment on Mycobacteria Avium Infections
治疗鸟分枝杆菌感染的新药
- 批准号:
10482476 - 财政年份:2022
- 资助金额:
$ 76.37万 - 项目类别:
Propargyl-linked Antifolates Targeting Klebsiella pneumoniae
针对肺炎克雷伯菌的炔丙基连接抗叶酸剂
- 批准号:
9178633 - 财政年份:2013
- 资助金额:
$ 76.37万 - 项目类别:
Propargyl-linked Antifolates Targeting Klebsiella pneumoniae
针对肺炎克雷伯菌的炔丙基连接抗叶酸剂
- 批准号:
8960331 - 财政年份:2013
- 资助金额:
$ 76.37万 - 项目类别:
HDAC Inhibitors Inspired by Natural Products
受天然产物启发的 HDAC 抑制剂
- 批准号:
8191877 - 财政年份:2011
- 资助金额:
$ 76.37万 - 项目类别:
HDAC Inhibitors Inspired by Natural Products
受天然产物启发的 HDAC 抑制剂
- 批准号:
8293024 - 财政年份:2011
- 资助金额:
$ 76.37万 - 项目类别:
STRATEGIC USE OF FURAN IN THE SYNTHESIS OF MOLECULES OF BIOLOGICAL IMPORTANCE
呋喃在具有生物重要性的分子合成中的战略用途
- 批准号:
7721467 - 财政年份:2008
- 资助金额:
$ 76.37万 - 项目类别:
相似海外基金
The earliest exploration of land by animals: from trace fossils to numerical analyses
动物对陆地的最早探索:从痕迹化石到数值分析
- 批准号:
EP/Z000920/1 - 财政年份:2025
- 资助金额:
$ 76.37万 - 项目类别:
Fellowship
Animals and geopolitics in South Asian borderlands
南亚边境地区的动物和地缘政治
- 批准号:
FT230100276 - 财政年份:2024
- 资助金额:
$ 76.37万 - 项目类别:
ARC Future Fellowships
The function of the RNA methylome in animals
RNA甲基化组在动物中的功能
- 批准号:
MR/X024261/1 - 财政年份:2024
- 资助金额:
$ 76.37万 - 项目类别:
Fellowship
Ecological and phylogenomic insights into infectious diseases in animals
对动物传染病的生态学和系统发育学见解
- 批准号:
DE240100388 - 财政年份:2024
- 资助金额:
$ 76.37万 - 项目类别:
Discovery Early Career Researcher Award
Zootropolis: Multi-species archaeological, ecological and historical approaches to animals in Medieval urban Scotland
Zootropolis:苏格兰中世纪城市动物的多物种考古、生态和历史方法
- 批准号:
2889694 - 财政年份:2023
- 资助金额:
$ 76.37万 - 项目类别:
Studentship
Using novel modelling approaches to investigate the evolution of symmetry in early animals.
使用新颖的建模方法来研究早期动物的对称性进化。
- 批准号:
2842926 - 财政年份:2023
- 资助金额:
$ 76.37万 - 项目类别:
Studentship
Study of human late fetal lung tissue and 3D in vitro organoids to replace and reduce animals in lung developmental research
研究人类晚期胎儿肺组织和 3D 体外类器官在肺发育研究中替代和减少动物
- 批准号:
NC/X001644/1 - 财政年份:2023
- 资助金额:
$ 76.37万 - 项目类别:
Training Grant
RUI: Unilateral Lasing in Underwater Animals
RUI:水下动物的单侧激光攻击
- 批准号:
2337595 - 财政年份:2023
- 资助金额:
$ 76.37万 - 项目类别:
Continuing Grant
RUI:OSIB:The effects of high disease risk on uninfected animals
RUI:OSIB:高疾病风险对未感染动物的影响
- 批准号:
2232190 - 财政年份:2023
- 资助金额:
$ 76.37万 - 项目类别:
Continuing Grant
A method for identifying taxonomy of plants and animals in metagenomic samples
一种识别宏基因组样本中植物和动物分类的方法
- 批准号:
23K17514 - 财政年份:2023
- 资助金额:
$ 76.37万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)