Characterization of MsbA inhibitors as potential antibiotic leads to treat carbapenem-resistant Enterobacteriaceae (CRE)

MsbA 抑制剂作为潜在抗生素的特性可用于治疗耐碳青霉烯类肠杆菌 (CRE)

基本信息

  • 批准号:
    9978345
  • 负责人:
  • 金额:
    $ 24.5万
  • 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:
    2020-08-19 至 2022-07-31
  • 项目状态:
    已结题

项目摘要

In 2013, the CDC designated carbapenem-resistant Enterobacteriaceae (CRE) an Urgent Threat, and in 2017, the WHO designated it a Priority 1 “critical superbug”. As few therapies remain to treat CRE, the risk of “pan- resistant” CRE untreatable by any currently available antibiotic also exists. Entirely new agents with novel mechanisms of action (MOA) not cross-resistant to SOC agents languish. Development of such a ‘first-in-class’ agent also offers the potential for much-needed orally-administered CRE therapeutic, thus providing a new step-down therapy to reduce hospital stay and growing healthcare costs. Our proposal aims to develop an entirely novel therapeutic to treat life-threatening bacterial infections due to multidrug resistant (MDR) Enterobacteriaceae, including CRE. Using an innovative overexpression-based co-culture screen in Escherichia coli (Ec), we identified four structurally distinct series of small molecule inhibitors targeting MsbA, an essential and broadly conserved Gram-negative (GN) ABC transporter responsible for lipopolysaccharide (LPS) biogenesis and construction of the Gram-negative outer membrane (OM). Building upon a solid foundation of preliminary data, our Aims are: Aim (A) 1. Expanded MOA studies. Aim 1 studies will expand upon our preliminary MOA and microbiological characterization of the MsbA inhibitor (MsbAi) hits to include other GN bacteria, particularly Klebsiella pneumoniae (Kp). Specifically, we will demonstrate Kp MsbA target inhibition in (1) an in vitro biochemical assay and (2) a whole-cell context by determining MICs of our MsbAis against a Kp tolC strain and subsequently selecting for MsbAisR mutants in this Kp background. Aim 2. Demonstrate chemical tractability of MsbAis. The goal of Aim 2 is to perform Hit to Lead (H2L) medicinal chemistry structure activity relationship (SAR) studies for each MsbAi and demonstrate >1 series is chemically tractable and that quantifiable pre-lead optimization criteria can be established, including i) Ec and Kp MsbA in vitro potency (IC50 < 0.25 µg/ml), ii) Ec and Kp WT activity (<16 µg/ml), and iii) > 90% HepG2 cell viability at 50X MIC against EcΔtolC. MsbAis achieving these milestones serve as a justifiable starting point for a future Lead Optimization leveraging the resulting SAR gained in Aim 2 and SBDD information from Aim 3. Aim 3. Obtain Ec and Kp MsbAi-MsbA co-crystal structures in collaboration with SSGCID. The goal of Aim 3 activities is to initiate a collaboration between Prokaryotics, Genentech, and the Seattle Structural Genomics Center for Infectious Disease (SSGCID) led by Dr. Peter Myler to optimize conditions suitable for obtaining high resolution x-ray crystal structures of Kp MsbA in the apo form as well as Ec and/or Kp MsbA proteins in complex with MsbAis.
2013年,CDC将碳青霉烯抗性肠杆菌科(CRE)列为紧急威胁,2017年,

项目成果

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Terry Roemer其他文献

Terry Roemer的其他文献

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{{ truncateString('Terry Roemer', 18)}}的其他基金

Development of a novel broad spectrum antifungal therapeutic targeting Glycosylphosphatidylinositol (GPI) biosynthesis and cell wall biogenesis
开发一种针对糖基磷脂酰肌醇 (GPI) 生物合成和细胞壁生物合成的新型广谱抗真菌治疗药物
  • 批准号:
    10759723
  • 财政年份:
    2023
  • 资助金额:
    $ 24.5万
  • 项目类别:
Development of a mechanistically novel synergistic adjuvant to partner with polymyxin antibiotics
开发一种与多粘菌素抗生素配合使用的新型机械协同佐剂
  • 批准号:
    10481682
  • 财政年份:
    2022
  • 资助金额:
    $ 24.5万
  • 项目类别:
Development of a mechanistically novel Gram-negative antibiotic targeting MsbA-mediated Lipopolysaccharide Biogenesis
开发一种机制新颖的革兰氏阴性抗生素,靶向 MsbA 介导的脂多糖生物发生
  • 批准号:
    10584170
  • 财政年份:
    2022
  • 资助金额:
    $ 24.5万
  • 项目类别:
Characterization of MsbA inhibitors as potential antibiotic leads to treat carbapenem-resistant Enterobacteriaceae (CRE)
MsbA 抑制剂作为潜在抗生素的特性可用于治疗耐碳青霉烯类肠杆菌 (CRE)
  • 批准号:
    10242174
  • 财政年份:
    2020
  • 资助金额:
    $ 24.5万
  • 项目类别:
Development of WecA-targeting immune potentiators to treat carbapenem-resistant Enterobacteriaceae (CRE) infections
开发 WecA 靶向免疫增强剂来治疗碳青霉烯类耐药肠杆菌 (CRE) 感染
  • 批准号:
    10415522
  • 财政年份:
    2019
  • 资助金额:
    $ 24.5万
  • 项目类别:
Development of WecA-targeting immune potentiators to treat carbapenem-resistant Enterobacteriaceae (CRE) infections
开发 WecA 靶向免疫增强剂来治疗碳青霉烯类耐药肠杆菌 (CRE) 感染
  • 批准号:
    10470327
  • 财政年份:
    2019
  • 资助金额:
    $ 24.5万
  • 项目类别:
Development of a novel agent to treat antimicrobial resistant Neisseria gonorrhoeae
开发治疗耐药性淋病奈瑟菌的新型药物
  • 批准号:
    9620389
  • 财政年份:
    2018
  • 资助金额:
    $ 24.5万
  • 项目类别:
Restoring Beta-lactam efficacy against methicillin-resistant Staphylococci
恢复 β-内酰胺对耐甲氧西林葡萄球菌的功效
  • 批准号:
    9814432
  • 财政年份:
    2018
  • 资助金额:
    $ 24.5万
  • 项目类别:
Development of a PO-administered beta-lactam-tarocin combination agent to treat methicillin susceptible and methicillin resistant Staphylococci
开发用于治疗甲氧西林敏感和甲氧西林耐药葡萄球菌的 PO 给药 β-内酰胺-塔罗辛组合药物
  • 批准号:
    10662488
  • 财政年份:
    2018
  • 资助金额:
    $ 24.5万
  • 项目类别:
Development of a PO-administered beta-lactam-tarocin combination agent to treat methicillin susceptible and methicillin resistant Staphylococci
开发用于治疗甲氧西林敏感和甲氧西林耐药葡萄球菌的 PO 给药 β-内酰胺-塔罗辛组合药物
  • 批准号:
    10547079
  • 财政年份:
    2018
  • 资助金额:
    $ 24.5万
  • 项目类别:

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健康和疾病中的 ATP 结合盒转运蛋白
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