Synthesis and Evaluation of Narrow-Spectrum Antibiotics Targeting MRSA

针对MRSA的窄谱抗生素的合成与评价

基本信息

  • 批准号:
    9981542
  • 负责人:
  • 金额:
    $ 14.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-01 至 2020-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Natural products account for two-thirds of the antibacterial pharmacopeia and are therefore privileged scaffolds. These complex molecules have inspired novel synthetic methods and positively impacted the fields of biochemistry, molecular biology, and medicine. The proposed project is inspired by albocycline, a unique 14-membered macrolactone with potent, narrow-spectrum activity against the “superbug” methicillin- resistant Staphylococcus aureus (MRSA). We have validated that albocycline is effective against MRSA and vancomycin-resistant S. aureus strains; moreover, it is non-toxic to human cells. In 2013, Tomoda reported that albocycline inhibited peptidoglycan (i.e., bacterial cell wall) synthesis in macromolecular assays. Using biochemical assays and molecular modeling, we demonstrated that albocycline was a weak (mM) inhibitor of MurA from S. aureus. Consistent with its narrow-spectrum profile, albocycline did not inhibit MurA from E. coli. Based on our results and those of Tomoda, we conclude it must have additional bacterial targets. Significantly, we recently completed a modular, step-efficient total synthesis of the natural product driven by novel chemistry of N-sulfinyl metallodienamines. Accordingly, in Aim 1 we propose to prepare albocycline analogs (including probes) by semi- and diverted total synthesis to explore the chemical space about this privileged scaffold. In Aim 2, we will co-crystallize albocycline in complex with MurA based on exciting preliminary results and employ structure-based analog design. We will also identify the target(s) of albocycline to determine its mode-of-action using computational chemistry, chemical proteomics and genomics approaches, in addition to a novel metabolic labeling methodology. Finally, in Aim 3 we will evaluate the biological activity of all albocycline analogs. At the end of the four-year project period, we will have (1) a deeper understanding of how albocycline exerts its antibacterial action; (2) a library of tool compounds and antibiotic lead candidates that selectively modulate their target(s); and most significantly, (3) a bona fide launching point for the development of novel, narrow-spectrum antibiotics to treat recalcitrant MRSA, VISA, and VRSA (i.e., the project's long-term goal).
项目总结/文摘

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Synthesis and biological evaluation of semi-synthetic albocycline analogs.
  • DOI:
    10.1016/j.bmcl.2020.127509
  • 发表时间:
    2020-11-01
  • 期刊:
  • 影响因子:
    2.7
  • 作者:
    Daher SS;Franklin KP;Scherzi T;Dunman PM;Andrade RB
  • 通讯作者:
    Andrade RB
Alternative approaches utilizing click chemistry to develop next-generation analogs of solithromycin.
  • DOI:
    10.1016/j.ejmech.2022.114213
  • 发表时间:
    2022-04-05
  • 期刊:
  • 影响因子:
    6.7
  • 作者:
    Daher, Samer S.;Lee, Miseon;Jin, Xiao;Teijaro, Christiana N. N.;Barnett, Pamela R. R.;Freundlich, Joel S. S.;Andrade, Rodrigo B. B.
  • 通讯作者:
    Andrade, Rodrigo B. B.
Staphylococcus aureus resistance to albocycline can be achieved by mutations that alter cellular NAD/PH pools.
  • DOI:
    10.1016/j.bmc.2021.115995
  • 发表时间:
    2021-02-15
  • 期刊:
  • 影响因子:
    3.5
  • 作者:
    Scherzi T;D'Ambrosio EA;Daher SS;Grimes CL;Dunman PM;Andrade RB
  • 通讯作者:
    Andrade RB
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RODRIGO B ANDRADE其他文献

RODRIGO B ANDRADE的其他文献

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{{ truncateString('RODRIGO B ANDRADE', 18)}}的其他基金

Discovery of Novel Macrolide Antibiotics
新型大环内酯类抗生素的发现
  • 批准号:
    7566407
  • 财政年份:
    2009
  • 资助金额:
    $ 14.5万
  • 项目类别:
Discovery of Novel Macrolide Antibiotics
新型大环内酯类抗生素的发现
  • 批准号:
    7891283
  • 财政年份:
    2009
  • 资助金额:
    $ 14.5万
  • 项目类别:
Discovery of Novel Macrolide Antibiotics
新型大环内酯类抗生素的发现
  • 批准号:
    8089259
  • 财政年份:
    2009
  • 资助金额:
    $ 14.5万
  • 项目类别:
Discovery of Novel Macrolide Antibiotics
新型大环内酯类抗生素的发现
  • 批准号:
    8288248
  • 财政年份:
    2009
  • 资助金额:
    $ 14.5万
  • 项目类别:
Enantioselective Total Synthesis of (+)-Halichlorine
( )-卤氯的对映选择性全合成
  • 批准号:
    6847444
  • 财政年份:
    2004
  • 资助金额:
    $ 14.5万
  • 项目类别:
Enantioselective Total Synthesis of (+)-Halichlorine
( )-卤氯的对映选择性全合成
  • 批准号:
    6742018
  • 财政年份:
    2004
  • 资助金额:
    $ 14.5万
  • 项目类别:

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