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首页> 外文期刊>Nature >Activated ClpP kills persisters and eradicates a chronic biofilm infection
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Activated ClpP kills persisters and eradicates a chronic biofilm infection

机译：激活的ClpP可杀死持久性物质并消除慢性生物膜感染

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摘要

细菌药物反应的双重性质使人们更加担心今天的抗生素应对未来感染的能力。一些细菌会形成遗传抗性，而其他的则会通过形成被称为"persister"的休眠细胞（在这种细胞中抗生素的酶目标是失活的）而变得具有耐受性，能够在抗生素存在下存活。Kim Lewis及同事进行了搜寻有可能通过破坏这些能量有限的细胞内的目标来杀灭persister细胞的药物的研究工作。他们发现，acyldepsipeptide抗生素ADEP4能激发CIpP蛋白酶和细胞的蛋白水解机制，通过迫使persister细胞降解一系列细胞蛋白来杀灭它们。这是一个有潜在重要性的结果，它表明：将ADEP4这样的药物与传统抗生素相结合，有可能为慢性感染的控制提供新的可靠策略。%Chronic infections are difficult to treat with antibiotics but are caused primarily by drug-sensitive pathogens. Dormant persister cells that are tolerant to killing by antibiotics are responsible for this apparent paradox. Persisters are phenotypic variants of normal cells and pathways leading to dormancy are redundant, making it challenging to develop anti-persister compounds. Biofilms shield persisters from the immune system, suggesting that an antibiotic for treating a chronic infection should be able to eradicate the infection on its own. We reasoned that a compound capable of corrupting a target in dormant cells will kill persisters. The acyldepsipeptide antibiotic (ADEP4) has been shown to activate the ClpP protease, resulting in death of growing cells. Here we show that ADEP4-activated ClpP becomes a fairly nonspecific protease and kills persisters by degrading over 400 proteins, forcing cells to self-digest. Null mutants of clpP arise with high probability, but combining ADEP4 with rifampicin produced complete eradication of Staphylococcus aureus biofilms in vitro and in a mouse model of a chronic infection. Our findings indicate a general principle for killing dormant cells-activation and corruption of a target, rather than conventional inhibition. Eradication of a biofilm in an animal model by activating a protease suggests a realistic path towards developing therapies to treat chronic infections.
机译：细菌药物反应的双重性质使人们更加担心今天的抗生素应对未来感染的能力。一些细菌会形成遗传抗性，而其他的则会通过形成被称为"persister"的休眠细胞（在这种细胞中抗生素的酶目标是失活的）而变得具有耐受性，能够在抗生素存在下存活。Kim Lewis及同事进行了搜寻有可能通过破坏这些能量有限的细胞内的目标来杀灭persister细胞的药物的研究工作。他们发现，acyldepsipeptide抗生素ADEP4能激发CIpP蛋白酶和细胞的蛋白水解机制，通过迫使persister细胞降解一系列细胞蛋白来杀灭它们。这是一个有潜在重要性的结果，它表明：将ADEP4这样的药物与传统抗生素相结合，有可能为慢性感染的控制提供新的可靠策略。%Chronic infections are difficult to treat with antibiotics but are caused primarily by drug-sensitive pathogens. Dormant persister cells that are tolerant to killing by antibiotics are responsible for this apparent paradox. Persisters are phenotypic variants of normal cells and pathways leading to dormancy are redundant, making it challenging to develop anti-persister compounds. Biofilms shield persisters from the immune system, suggesting that an antibiotic for treating a chronic infection should be able to eradicate the infection on its own. We reasoned that a compound capable of corrupting a target in dormant cells will kill persisters. The acyldepsipeptide antibiotic (ADEP4) has been shown to activate the ClpP protease, resulting in death of growing cells. Here we show that ADEP4-activated ClpP becomes a fairly nonspecific protease and kills persisters by degrading over 400 proteins, forcing cells to self-digest. Null mutants of clpP arise with high probability, but combining ADEP4 with rifampicin produced complete eradication of Staphylococcus aureus biofilms in vitro and in a mouse model of a chronic infection. Our findings indicate a general principle for killing dormant cells-activation and corruption of a target, rather than conventional inhibition. Eradication of a biofilm in an animal model by activating a protease suggests a realistic path towards developing therapies to treat chronic infections.

著录项

  • 来源
    《Nature》 |2013年第7476期|365-370a3|共7页
  • 作者

    B. P. Cordon; E. S. Nakayasu; L. E. Fleck; M. D. LaFleur; V. M. Isabella; K. Coleman; S. N. Leonard; R. D. Smith; J. N. Adkins; K. Lewis;

  • 作者单位

    Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts 02115, USA;

    Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, USA,Bindley Bioscience Center, Purdue University, West Lafayette, Indiana 47907, USA;

    Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts 02115, USA;

    Arietis Corporation, Boston, Massachusetts 02118, USA;

    Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts 02115, USA;

    Arietis Corporation, Boston, Massachusetts 02118, USA;

    Bouve College of Health Sciences, School of Pharmacy, Northeastern University, Boston, Massachusetts 02115, USA;

    Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, USA;

    Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, USA;

    Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts 02115, USA;

  • 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);
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