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Promysalin Elicits Species-Selective Inhibition of Pseudomonas aeruginosa by Targeting Succinate Dehydrogenase

机译:早霉素通过靶向琥珀酸脱氢酶引起铜绿假单胞菌的物种选择性抑制。

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摘要

Natural products have served as an inspiration to scientists both for their complex three-dimensional architecture and exquisite biological activity. Promysalin is one such Pseudomonad secondary metabolite that exhibits narrow-spectrum antibacterial activity, originally isolated from the rhizosphere. We herein utilize affinity-based protein profiling (AfBPP) to identify succinate dehydrogenase (Sdh) as the biological target of the natural product. The target was further validated in silico, in vitro, in vivo, and through the selection, and sequencing, of a resistant mutant. Succinate dehydrogenase plays an essential role in primary metabolism of Pseudomonas aeruginosa as the only enzyme that is involved both in the tricarboxylic acid cycle (TCA) and in respiration via the electron transport chain. These findings add credence to other studies that suggest that the TCA cycle is an understudied target in the development of novel therapeutics to combat P. aeruginosa , a significant pathogen in clinical settings.
机译:天然产物因其复杂的三维结构和精美的生物活性而激发了科学家的灵感。早稻激肽是一种这样的假单胞菌次级代谢产物,它具有窄谱抗菌活性,最初是从根际分离出来的。我们在本文中利用基于亲和力的蛋白质谱(AfBPP)来鉴定琥珀酸脱氢酶(Sdh)作为天然产物的生物学目标。通过抗性突变体的筛选和测序,在计算机上,体外,体内进一步验证了靶标。琥珀酸脱氢酶在铜绿假单胞菌的初级代谢中起着重要作用,因为它是唯一参与三羧酸循环(TCA)和通过电子传输链呼吸的酶。这些发现为其他研究提供了可信度,这些研究表明,TCA循环是对抗铜绿假单胞菌(临床环境中的重要病原体)的新型疗法的开发中未被充分研究的目标。

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  • 来源
    《Journal of the American Chemical Society》 |2018年第5期|1774-1782|共9页
  • 作者单位

    Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States;

    Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States;

    Department of Chemistry, Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Lichtenbergstraße 4, 85747 Garching, Germany;

    Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, United States,Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66045, United States;

    Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02115, United States,Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, United States;

    Division of Structural Biology, The University of Oxford, Headington Oxford, OX3 7BN, United Kingdom,Biomedical Sciences Research Complex, University of St. Andrews, Fife Scotland, KY16 9ST, United Kingdom;

    Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02115, United States,Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, United States;

    Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, United States;

    Department of Chemistry, Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Lichtenbergstraße 4, 85747 Garching, Germany;

    Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 入库时间 2022-08-18 03:07:18

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