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

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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

1. Bruni GN
2. Kralj JM
(2020) E. coli aminoglycoside treatment
doi:10.5061/dryad.fxpnvx0pp.

http://dx.doi.org/10.5061/dryad.fxpnvx0pp

Article and author information

Author details

Giancarlo Noe Bruni

BioFrontiers/MCDB, University of Colorado - Boulder, Boulder, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2850-4633
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.

"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.

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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.