Membrane voltage dysregulation driven by metabolic dysfunction underlies bactericidal activity of aminoglycosides

  1. Giancarlo Noe Bruni
  2. Joel Kralj  Is a corresponding author
  1. University of Colorado - Boulder, United States

Abstract

Aminoglycosides are broad-spectrum antibiotics whose mechanism of action is under debate. It is widely accepted that membrane voltage potentiates aminoglycoside activity, which is ascribed to voltage-dependent drug uptake. In this paper, we measured the response of Escherichia coli treated with aminoglycosides and discovered that the bactericidal action arises not from the downstream effects of voltage dependent drug uptake, but rather directly from dysregulated membrane potential. In the absence of voltage, aminoglycosides are taken into cells and exert bacteriostatic effects by inhibiting translation. However, cell killing was immediate upon re-polarization. The hyperpolarization arose from altered ATP flux, which induced a reversal of the F1Fo-ATPase to hydrolyze ATP and generated the deleterious voltage. Heterologous expression of an ATPase inhibitor completely eliminated bactericidal activity, while loss of the F-ATPase reduced the electrophysiological response to aminoglycosides. Our data support a model of voltage induced death, and separates aminoglycoside bacteriostasis and bactericide in E. coli.

Data availability

All data have been submitted on Dryad.

The following data sets were generated

Article and author information

Author details

  1. Giancarlo Noe Bruni

    BioFrontiers/MCDB, University of Colorado - Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2850-4633
  2. Joel Kralj

    BioFrontiers/MCDB, University of Colorado - Boulder, Boulder, United States
    For correspondence
    joel.kralj@colorado.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9370-2324

Funding

Howard Hughes Medical Institute (Gilliam Fellowship for advanced study)

  • Giancarlo Noe Bruni

Kinship Foundation (Searle Scholar Award)

  • Joel Kralj

National Institute of General Medical Sciences (T32GM065103)

  • Giancarlo Noe Bruni

National Institute of General Medical Sciences (1DP2GM123458)

  • Joel Kralj

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Michael T Laub, Massachusetts Institute of Technology, United States

Version history

  1. Received: May 8, 2020
  2. Accepted: July 24, 2020
  3. Accepted Manuscript published: August 4, 2020 (version 1)
  4. Version of Record published: August 5, 2020 (version 2)

Copyright

© 2020, Bruni & Kralj

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Giancarlo Noe Bruni
  2. Joel Kralj
(2020)
Membrane voltage dysregulation driven by metabolic dysfunction underlies bactericidal activity of aminoglycosides
eLife 9:e58706.
https://doi.org/10.7554/eLife.58706

Share this article

https://doi.org/10.7554/eLife.58706

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