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Epoxytiglianes potentiate the activity of colistin against resistant Escherichia coli via modification of the bacterial cell membrane

Manon F. Pritchard Orcid Logo, Wenya Xue Orcid Logo, Jingxiang Wu Orcid Logo, Francesca Boardman Orcid Logo, Mei Li Orcid Logo, Yuqing Zhou Orcid Logo, Saira Khan Orcid Logo, Lydia Powell Orcid Logo, Joana Stokniene Orcid Logo, Josh Davies-Jones Orcid Logo, Philip R. Davies Orcid Logo, Niklaas J. Buurma Orcid Logo, Georgina E. Menzies Orcid Logo, Owen B. Spiller Orcid Logo, Timothy R. Walsh Orcid Logo, Paul Reddell Orcid Logo, Katja E. Hill Orcid Logo, David W. Thomas Orcid Logo

mBio, Start page: e02314-25

Swansea University Author: Lydia Powell Orcid Logo

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DOI (Published version): 10.1128/mbio.02314-25

Abstract

The unrestricted use of colistin in animal husbandry has led to the emergence of mobile plasmid-borne colistin resistance (mcr). The antimicrobial epoxytigliane, EBC-1013, has been shown to be effective in the topical treatment of biofilm-mediated infections in vivo . Hypothesizing that EBC-1013 int...

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Published in: mBio
ISSN: 2150-7511
Published: American Society for Microbiology 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa71217
Abstract: The unrestricted use of colistin in animal husbandry has led to the emergence of mobile plasmid-borne colistin resistance (mcr). The antimicrobial epoxytigliane, EBC-1013, has been shown to be effective in the topical treatment of biofilm-mediated infections in vivo . Hypothesizing that EBC-1013 interacts with the modified bacterial outer membrane of colistin-resistant Escherichia coli, we investigated its ability to potentiate the activity of colistin using fractional inhibitory concentration (FIC) index determinations against environmental mcr Enterobacteriaceae. Molecular dynamics (MD) simulations were used to visualize EBC-1013 interactions with the outer membrane in silico . Modification of outer membrane surface chemistry and adhesion properties was characterized using X-ray photoelectron spectroscopy (XPS) and hydrophobicity and bacterial membrane permeability assays. Anti-biofilm activity was quantified using confocal laser scanning microscopy (CLSM). Checkerboard assays revealed synergistic effects of EBC-1013 with colistin (FIC ≤ 0.5) in 6/9 strains. MD simulations demonstrated weak EBC-1013 interactions with colistin and the outer membrane. XPS suggested modification of the outer membrane in both colistin-sensitive and colistin-resistant E. coli, as well as the interaction of colistin and EBC-1013 with the phosphoethanolamine (pEtN)-substituted mcr lipid moiety. EBC-1013 binding significantly decreased bacterial hydrophilicity and potentiated membrane permeability induced by colistin (P < 0.05). In the biofilm model, potentiation was also evident, with a marked decrease in bacterial biomass in EBC-1013/colistin combined treatments (P < 0.0001) for colistin-resistant E. coli . The results highlight the ability of EBC-1013 to modify the bacterial membrane of colistin-resistant E. coli and potentiate the activity of colistin in the treatment of multidrug-resistant wound bacteria. IMPORTANCE Resistance to colistin, an antibiotic of last resort for hard-to-treat infections, is on the increase. Therefore, the need to develop new antimicrobials to tackle antimicrobial resistance is of paramount importance. The epoxytiglianes represent an exciting range of molecules with a diverse range of biological effects in human and veterinary applications, including antimicrobial properties. In this study, we show how EBC-1013 interacts with the outer surface of colistin-resistant Escherichia coli cells, inducing chemical and structural changes to the cell wall, making it susceptible again to colistin treatment. This ability of EBC-1013 to enhance the activity of colistin against a range of colistin-resistant E. coli suggests that EBC-1013, alone (or as a combination therapy), has potential as a new treatment strategy to treat antibiotic-resistant bacterial wound infections and reduce antibiotic usage. This study is registered with ClinicalTrials.gov as (Australian New Zealand Clinical Trials Register: ACTRN12624000544572 ).
Keywords: antimicrobial resistance (AMR), plasmid, mcr-1, mcr-3
College: Faculty of Medicine, Health and Life Sciences
Funders: This work was funded by the ACCELERATE East program and the European Regional Development Fund under grant number 515454 (to D.W.T. and L.C.P.). This work also received support from QBiotics Group Ltd. (to L.C.P., M.F.P., K.E.H., and D.W.T.) and through a Ph.D. studentship for W.X.
Start Page: e02314-25

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