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Metabolite-enabled eradication of bacterial persisters by aminoglycosides

Nature volume 473, pages 216–220 (2011)Cite this article

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Abstract

Bacterial persistence is a state in which a sub-population of dormant cells, or ‘persisters’, tolerates antibiotic treatment1,2,3,4. Bacterial persisters have been implicated in biofilms and in chronic and recurrent infections5,6,7. 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.

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Figure 1: Specific metabolites enable killing of E. coli persisters by aminoglycosides.
Figure 2: Metabolite-enabled aminoglycoside uptake and bacterial killing requires PMF produced by the oxidative electron transport chain.
Figure 3: Mechanism for metabolite-enabled eradication of persisters (a) and clinically relevant experiments (b–d).
Figure 4: Fructose induces PMF-dependent killing of S. aureus persisters by an aminoglycoside.

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Acknowledgements

We thank A. Slee and T. Murphy from ViviSource Laboratories for assistance with the in vivo mouse studies and T. K. Lu for guidance with the biofilm experiments. This work was supported by the NIH Director’s Pioneer Award Program and the Howard Hughes Medical Institute.

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Author notes

  1. Mark P. Brynildsen

    Present address: Present address: Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey 08544, USA.,

Authors and Affiliations

  1. Department of Biomedical Engineering, Howard Hughes Medical Institute, Center for Biodynamics and Center for Advanced Biotechnology, Boston University, Boston, 02215, Massachusetts, USA

    Kyle R. Allison, Mark P. Brynildsen & James J. Collins

  2. Boston University School of Medicine, 715 Albany Street, Boston, 02118, Massachusetts, USA

    James J. Collins

  3. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, 02118, Massachusetts, USA

    James J. Collins

Authors
  1. Kyle R. Allison
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Contributions

All authors designed the study, analysed results and wrote the manuscript. Experiments were performed by K.R.A. and M.P.B.

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Correspondence to James J. Collins.

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The authors declare no competing financial interests.

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Allison, K., Brynildsen, M. & Collins, J. Metabolite-enabled eradication of bacterial persisters by aminoglycosides. Nature 473, 216–220 (2011). https://doi.org/10.1038/nature10069

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