Metabolite-Enabled Eradication of Bacterial Persisters by Aminoglycosides

By K. Allison, M. P. Brynildsen, James J. Collins. Nature, 2011

964 citations recorded by the source corpus.

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.

Subfields: Ecology, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ecf89bc415836743d2545814dc366135093e72c2

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Citations in the corpus

Silver Enhances Antibiotic Activity Against Gram-negative Bacteria (2013, background): “This has stimulated research to find viable ways to treat and eliminate bacteria persisters (48, 49).”
Antibiotics induce redox-related physiological alterations as part of their lethality (2014, background): “Indeed, recent work demonstrates that metabolic perturbations (102) or ROS elevation (92) can improve bactericidal lethality.”
Antibiotic resistance and persistence—Implications for human health and treatment perspectives (2020, positive): “Simple sugars like mannitol, fructose and glucose combined with gentamicin can decrease persister levels more than 1,000-fold in E. coli and S. aureus not via activating bacterial growth, but by increasing the pmf that in turn increases the uptake of aminoglycosides (Allison et al , 2011) (Fig 5B).”
Surviving as a community: antibiotic tolerance and persistence in bacterial biofilms (2019, background): “aureus persister cells in biofilms can be re-sensitized to an aminoglycoside antibiotic by providing metabolites that generate a proton-motive force facilitating aminoglycoside uptake (Allison et al., 2011).”
A white-box machine learning approach for revealing antibiotic mechanisms of action (2019, neutral): “extracellular metabolites may either potentiate (Allison et al., 2011; Meylan et al., 2017) or suppress (Yang et al.”
Bacterial Persister Cell Formation and Dormancy (2013, background): “, pyruvate) which serve to generate a proton motive force that makes the cells more susceptible to aminoglycosides (51); note that these authors did not show that these compounds revert persister cells.”
Molecular mechanisms underlying bacterial persisters. (2014, neutral): “coli) andGram-positive (Staphylococcus aureus) bacterial populations (Allison et al., 2011).”
Biofilm-Related Infections: Bridging the Gap between Clinical Management and Fundamental Aspects of Recalcitrance toward Antibiotics (2014, background): “In the case of mannitol or fructose, the generation of NADH stimulates PMF through an increase in (86).”