Tofacitinib Analogs as Oxacillin Potentiators against MRSA

托法替尼类似物作为抗 MRSA 的苯唑西林增效剂

基本信息

项目摘要

Project Summary Methicillin (oxacillin)-resistant Staphylococcus aureus (MRSA) infections are among the most frequently occurring and dangerous antibiotic-resistant public health threat. Clinical resistance to all front-line MRSA antibiotics (i.e. vancomycin, linezolid, daptomycin, and ceftaroline) has been observed, further exacerbating this threat and highlighting the urgent need for new strategies to overcome drug resistance in S. aureus. In recent years, there has been increased interest in targeting signal transduction systems for development as antimicrobials and anti-virulence agents. Targeting bacterial signal transduction is attractive because these systems are essential for many cellular processes in prokaryotes, and signal transduction pathways have been extensively studied in eukaryotic systems, as evidenced by the availability of chemical libraries containing small molecule probes with kinase inhibitor-like properties. With this strategy in mind, we screened a focused set of kinase inhibitors and identified tofacitinib, an antirheumatic Janus kinase inhibitor, as a potential chemistry starting point for the discovery of beta-lactam potentiators against MRSA. Several pyrrolopyridin-4- amine (P4A) analogs of tofacitinib were synthesized, which led to the discovery of potent analogs with the ability to re-sensitize oxacillin (OXA; a beta-lactam antibiotic) against MRSA. Preliminary pull-down proteomic experiments have identified PurM, SrrB, and PknB as putative targets, studies that have been complemented by gene knockout experiments. Therefore, the main scientific objective of this proposal is to confirm P4A engagement of putative targets using biophysical and biochemical techniques and to establish the therapeutic potential of tofacitinib analogs as anti-virulence agents and OXA potentiators against MRSA. In Aim 1, I will evaluate the binding of lead P4A compounds to putative targets, demonstrate inhibition of S. aureus kinase activity and determine the extent of potential off-target effects on mammalian kinases. Biophysical assays will be developed against the putative targets through a novel target engagement assay, which will be complemented with biochemical phosphorylation and ATP/ADP conversion assays. In Aim 2, I will evaluate the clinical potential of the P4A compounds through anti-biofilm studies, pharmacological ADME profiling, and in vivo efficacy against MRSA in a mouse model. The research plan will enhance my training in areas of target identification and validation, biophysical analysis, and anti-infective microbiology, benefiting from the expertise of my co-mentors, Drs. Richard Lee and Jason Rosch, and the state-of-the-art resources at St. Jude.
项目概要 耐甲氧西林(苯唑西林)金黄色葡萄球菌 (MRSA) 感染是最常见的感染之一 正在发生的危险的抗生素耐药性公共卫生威胁。对所有一线 MRSA 的临床耐药性 已观察到抗生素(即万古霉素、利奈唑胺、达托霉素和头孢洛林),进一步加剧了 这一威胁并强调迫切需要新的策略来克服金黄色葡萄球菌的耐药性。在 近年来,人们对以信号转导系统为目标的开发越来越感兴趣 抗菌剂和抗毒剂。靶向细菌信号转导很有吸引力,因为这些 系统对于原核生物的许多细胞过程至关重要,并且信号转导途径已被 在真核系统中进行了广泛的研究,化学文库的可用性证明了这一点 具有激酶抑制剂样特性的小分子探针。考虑到这一策略,我们筛选了一个重点 一组激酶抑制剂,并确定托法替尼(一种抗风湿 Janus 激酶抑制剂)作为潜在的 发现抗 MRSA 的 β-内酰胺增效剂的化学起点。几种吡咯并吡啶-4- 合成了托法替布的胺 (P4A) 类似物,从而发现了有效的类似物 使苯唑西林(OXA;一种 β-内酰胺抗生素)对 MRSA 重新敏感的能力。初步下拉蛋白质组学 实验已确定 PurM、SrrB 和 PknB 为假定靶标,这些研究已得到补充 通过基因敲除实验。因此,本提案的主要科学目标是确认P4A 使用生物物理和生化技术参与假定目标并建立 托法替布类似物作为抗毒剂和 OXA 增强剂的治疗潜力 耐甲氧西林金黄色葡萄球菌。在目标 1 中,我将评估先导 P4A 化合物与假定靶标的结合,证明抑制作用 金黄色葡萄球菌激酶活性并确定对哺乳动物激酶的潜在脱靶影响的程度。 将通过一种新颖的目标参与分析针对假定目标开发生物物理分析, 生化磷酸化和 ATP/ADP 转化测定将对其进行补充。在目标 2 中,我 将通过抗生物膜研究、药理学 ADME 评估 P4A 化合物的临床潜力 小鼠模型中针对 MRSA 的分析和体内功效。该研究计划将加强我的培训 目标识别和验证、生物物理分析和抗感染微生物学领域,受益 来自我的共同导师 Drs 的专业知识。 Richard Lee 和 Jason Rosch,以及最先进的资源 圣裘德。

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 }}

Gregory Phelps其他文献

Gregory Phelps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 }}

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:
    $ 4.37万
  • 项目类别:
    Fellowship
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:
    $ 4.37万
  • 项目类别:
    Research Grant
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:
    $ 4.37万
  • 项目类别:
    Continuing 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:
    $ 4.37万
  • 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:
    $ 4.37万
  • 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:
    $ 4.37万
  • 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:
    $ 4.37万
  • 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:
    $ 4.37万
  • 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:
    $ 4.37万
  • 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:
    $ 4.37万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了