Transport Mechanisms and Inhibition of Efflux Pumps in Pathogenic Organisms

病原生物外排泵的转运机制和抑制

基本信息

  • 批准号:
    10531273
  • 负责人:
  • 金额:
    $ 74.35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-12-01 至 2026-11-30
  • 项目状态:
    未结题

项目摘要

Project Summary The long-term goal of our research is to develop first-in-class, protein-based inhibitors against human bacterial pathogens by directly blocking efflux pumps. Drug resistant bacteria pose an urgent global health challenge by reducing the effectiveness of antibiotics used to treat infections in humans and animals. The broadest resistance mechanism against antibiotics are efflux pumps, which transport drugs out of the cytoplasm and reduce toxicity to the organism. While it is known that efflux pumps display broad specificity to structurally distinct compounds, the mechanisms of polyspecific drug binding and ion-coupled transport remain unanswered questions in the field. Given the promiscuity of efflux pump binding to structurally distinct drugs, it is also unclear whether potent and selective efflux pump inhibitors can be designed to target specific classes of efflux pumps. The specific goals of this project are to discover novel mechanisms of active transport in drug resistant Staphylococcus aureus and to harness this knowledge to design selective inhibitors toward efflux pumps. Our proposal is strongly motivated by our recent discovery of antibody fragments (Fabs) that bind the Staphylococcus aureus efflux pump NorA and successful determination of high-resolution cryoEM structures using the Fabs as fiduciaries. The structures revealed that the Fabs insert a loop into the substrate binding pocket from the extracellular side, which suggests a design path toward protein- and peptide-based inhibitors. This interaction is facilitated by an electrostatic interaction between a positively charged arginine on the Fab and two essential anionic residues within NorA. Building on these preliminary data, we propose to carry out four Specific Aims. Aim 1 will develop a hybrid approach of cryo-electron microscopy and NMR spectroscopy to comprehensively study the transport cycle of NorA. Aim 2 will seek to determine the molecular basis for polyspecific drug binding. Aim 3 will design and characterize protein-based inhibitors that target the accessible, outward-open conformation of NorA. Aim 4 will develop peptides that miniaturize the antibody loops observed in the binding pocket of NorA. We have assembled an interdisciplinary team with expertise in structural biology, protein engineering, microbiology, chemical synthesis, and computational chemistry to rapidly answer fundamental questions about multidrug transport and inhibition of efflux pumps. All of the approaches applied to NorA will be translatable to other transporter systems.
项目总结

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)

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SHOHEI KOIDE的其他文献

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{{ truncateString('SHOHEI KOIDE', 18)}}的其他基金

Novel biologics platform for targeting tumors driven by intracellular oncoproteins
用于靶向细胞内癌蛋白驱动的肿瘤的新型生物制剂平台
  • 批准号:
    10356663
  • 财政年份:
    2021
  • 资助金额:
    $ 74.35万
  • 项目类别:
Transport Mechanisms and Inhibition of Efflux Pumps in Pathogenic Organisms
病原生物外排泵的转运机制和抑制
  • 批准号:
    10344321
  • 财政年份:
    2021
  • 资助金额:
    $ 74.35万
  • 项目类别:
Novel biologics platform for targeting tumors driven by intracellular oncoproteins
用于靶向细胞内癌蛋白驱动的肿瘤的新型生物制剂平台
  • 批准号:
    10533364
  • 财政年份:
    2021
  • 资助金额:
    $ 74.35万
  • 项目类别:
Accurate prediction of neutralization capacity from deep mining of SARS-CoV-2 serology
深度挖掘SARS-CoV-2血清学,准确预测中和能力
  • 批准号:
    10195613
  • 财政年份:
    2020
  • 资助金额:
    $ 74.35万
  • 项目类别:
Probing RAS-mediated signaling mechanisms with monobody inhibitors
使用单体抑制剂探索 RAS 介导的信号传导机制
  • 批准号:
    9977135
  • 财政年份:
    2018
  • 资助金额:
    $ 74.35万
  • 项目类别:
Probing RAS-mediated signaling mechanisms with monobody inhibitors
使用单体抑制剂探索 RAS 介导的信号传导机制
  • 批准号:
    10220892
  • 财政年份:
    2018
  • 资助金额:
    $ 74.35万
  • 项目类别:
Probing RAS-mediated signaling mechanisms with monobody inhibitors
使用单体抑制剂探索 RAS 介导的信号传导机制
  • 批准号:
    9751810
  • 财政年份:
    2018
  • 资助金额:
    $ 74.35万
  • 项目类别:
Probing RAS-mediated signaling mechanisms with monobody inhibitors
使用单体抑制剂探索 RAS 介导的信号传导机制
  • 批准号:
    9384266
  • 财政年份:
    2017
  • 资助金额:
    $ 74.35万
  • 项目类别:
Probing RAS-mediated Signaling with Monobody Inhibitors
使用单体抑制剂探测 RAS 介导的信号转导
  • 批准号:
    10530818
  • 财政年份:
    2017
  • 资助金额:
    $ 74.35万
  • 项目类别:
Probing RAS-mediated Signaling with Monobody Inhibitors
使用单体抑制剂探测 RAS 介导的信号转导
  • 批准号:
    10666670
  • 财政年份:
    2017
  • 资助金额:
    $ 74.35万
  • 项目类别:

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