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Metabolite-enabled eradication of bacterial persisters by aminoglycosides

机译：氨基糖苷类代谢物可消除细菌残留

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摘要

Bacterial persistence is a state in which a sub-population of dormant cells, or 'persisters', tolerates antibiotic treatment. Bacterial persisters have been implicated in biofilms and in chronic and recurrent infections. Despite this clinical relevance, there are currently no viable means for eradicating persisters. Here we show that specific metabolic stimuli enable the killing of both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) persisters with aminoglycosides. This potentiation is aminoglycoside-specific, it does not rely on growth resumption and it is effective in both aerobic and anaerobic conditions. It proceeds by the generation of a proton-motive force which facilitates aminoglycoside uptake. Our results demonstrate that persisters, although dormant, are primed for metabolite uptake, central metabolism and respiration. We show that aminoglycosides can be used in combination with specific metabolites to treat E. coli and S. aureus biofilms. Furthermore, we demonstrate that this approach can improve the treatment of chronic infections in a mouse urinary tract infection model. This work establishes a strategy for eradicating bacterial persisters that is based on metabolism, and highlights the importance of the metabolic environment to antibiotic treatment.
机译：细菌持久性是休眠细胞亚群或“持久性细胞”耐受抗生素治疗的状态。细菌持久性物质与生物膜以及慢性和复发性感染有关。尽管具有这种临床相关性，但目前尚无可行的方法来消除持久性物质。在这里，我们显示特定的代谢刺激能够杀死氨基糖苷类的革兰氏阴性菌（大肠杆菌）和革兰氏阳性菌（金黄色葡萄球菌）。这种增强作用是氨基糖苷特异性的，它不依赖于恢复生长，并且在有氧和厌氧条件下均有效。它通过产生促进氨基糖苷摄取的质子动力来进行。我们的研究结果表明，持久性物质虽然处于休眠状态，但主要用于代谢物的吸收，中枢代谢和呼吸作用。我们表明，氨基糖苷类可以与特定的代谢产物结合使用，以治疗大肠杆菌和金黄色葡萄球菌生物膜。此外，我们证明了这种方法可以改善小鼠尿路感染模型中慢性感染的治疗。这项工作建立了一种基于代谢的消除细菌残留的策略，并强调了代谢环境对抗生素治疗的重要性。

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  • 来源
    《Nature》 |2011年第7346期|p.216-220|共5页
  • 作者

    Kyle R. Allison; Mark P. Brynildsen; James J. Collins;

  • 作者单位

    Howard Hughes Medical Institute, Department of Biomedical Engineering,CenterforBiodynamics and Centerfor Advanced Biotechnology, Boston University,Boston, Massachusetts 02215, USA;

    Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey 08544, USA;

    Howard Hughes Medical Institute, Department of Biomedical Engineering,CenterforBiodynamics and Centerfor Advanced Biotechnology, Boston University,Boston, Massachusetts 02215, USA,Boston University School of Medicine, 715 Albany Street, Boston, Massachusetts 02118, USA,Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02118, 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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  • 正文语种 eng
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