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Antimicrobials

Energizing antibiotic killing

Nature Reviews Microbiology volume 23, page 753 (2025)Cite this article

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Polymyxins are clinically used antibiotics that target lipopolysaccharides (LPSs) in the membranes of Gram-negative bacteria, leading to membrane disruption; however, the underlying mechanisms that lead to bacterial killing are not well understood. Another outstanding question is whether metabolic activity is required for the activity and efficacy of polymyxins, and the available data are inconsistent. In a recent study, Edwards, Hoogenboom and colleagues show that metabolic inactivity confers tolerance against polymyxin antibiotics, and they propose a model for polymyxin-mediated killing of metabolically active bacterial cells.

They went on to examine antibiotic-induced changes to the outer membrane and report that LPSs were lost from cells that had been exposed to polymyxin B in the presence of glucose but not in the absence of the antibiotic or glucose. So, is there a link between the observed dependence on metabolic activity and LPS loss? Indeed, the authors were able to show that polymyxin B triggers LPS release via a process that requires ATP-dependent synthesis and transport of LPSs. Importantly, the authors found that the polymyxin B-mediated loss of LPSs alone was not sufficient to kill the bacteria, but that the antibiotic-triggered, energy-dependent release of LPSs enabled entry of polymyxin B into the periplasm, thereby gaining access to the inner membrane and leading to membrane disruption and cell death. In support of this model, the induction of LPS loss in metabolically inactive cells through the addition of EDTA (which can destabilize the outer membrane) together with exposure to the antibiotic led to cell death.

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  1. Nature Reviews Microbiology http://www.nature.com/nrmicro/

    Andrea Du Toit

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  1. Andrea Du Toit
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Correspondence to Andrea Du Toit.

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Du Toit, A. Energizing antibiotic killing. Nat Rev Microbiol 23, 753 (2025). https://doi.org/10.1038/s41579-025-01252-0

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