Work

Polymyxin B lethality requires energy-dependent outer membrane disruption

Year: 2025

Type: article

Abstract: Polymyxin antibiotics target lipopolysaccharides (LPSs) in both membranes of the bacterial cell envelope, leading to bacterial killing through a poorly defined mechanism. Here we demonstrate that metabolic activity is essential for the lethality of clinically relevant doses of polymyxin B (PmB) and leverage this insight to determine its mode of action. PmB killed exponential-phase Escherichia coli but did not eliminate stationary-phase cells unless a carbon source was available. Antibiotic lethality correlated with surface protrusions visible by atomic force microscopy and LPS loss from the outer membrane via processes that required LPS synthesis and transport but that were blocked by the MCR-1 polymyxin resistance determinant. While energy-dependent outer-membrane disruption was not directly lethal, it facilitated PmB access to the inner membrane, which the antibiotic permeabilized in an energy-independent manner, leading to cell death. This work reveals how metabolic inactivity confers tolerance of an important, membrane-targeting antibiotic.

Source: Nature Microbiology

DOI: 10.1038/s41564-025-02133-1

Authors: Carolina Borrelli, Edward J. A. Douglas, Sophia M. A. Riley, Aikaterini Ellas Lemonidi, Gerald Larrouy-Maumus, Wen-Jung Lu, Boyan B. Bonev, Andrew M. Edwards, Bart W. Hoogenboom

Institutions: London Centre for Nanotechnology, University College London, Imperial College London, University of Nottingham, Queen's Medical Centre

Language: English

Topic: Bacterial Genetics and Biotechnology

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $12,690

Funders: Wellcome Trust, Research Councils UK, Science Foundation Ireland, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council

Awards: G1015516259, G1551222207, G1740809987, G17884602, G1959076559, (re)Defining the nature of the Gram-negative outer membrane, High-speed High-throughput AFM For Cell And Developmental Biology, EPSRC and SFI Centre for Doctoral Training in the Advanced Characterisation of Materials (CDT-ACM), Determining how polymyxins kill bacteria, Changes in structure and biogenesis of Gram-negative envelope following a polymyxin challenge, G6624705087, G6768371165, EPSRC IRC in Early-Warning Sensing Systems for Infectious Diseases, Disruption in bacterial cell envelope following polymyxin challenge and adaptations in tolerant strains, G8506606079, Disruption And Resistance In Bacterial Cell Envelopes Challenged By Polymyxins

OpenAlex ID: W4414687283

FWCI: 19.33

Cites: 98

Cited by: 36

Related to: