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

Pritchard, Manon F. ORCID: https://orcid.org/0000-0002-5135-4744, Xue, Wenya, Wu, Jingxiang, Boardman, Francesca, Li, Mei, Zhou, Yuqing, Khan, Saira, Powell, Lydia C. ORCID: https://orcid.org/0000-0002-8641-0160, Stokniene, Joana, Davies-Jones, Josh, Davies, Philip R. ORCID: https://orcid.org/0000-0003-4394-766X, Buurma, Niklaas J. ORCID: https://orcid.org/0000-0003-0260-5057, Menzies, Georgina E. ORCID: https://orcid.org/0000-0002-6600-6507, Spiller, Owen B. ORCID: https://orcid.org/0000-0002-9117-6911, Walsh, Timothy R., Reddell, Paul, Hill, Katja E. ORCID: https://orcid.org/0000-0002-8590-0117 and Thomas, David W. ORCID: https://orcid.org/0000-0001-7319-5820 2025. Epoxytiglianes potentiate the activity of colistin against resistant Escherichia coli via modification of the bacterial cell membrane. mBio 10.1128/mbio.02314-25

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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.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Biosciences Research Institutes & Centres > Cardiff Catalysis Institute (CCI) Schools > Chemistry Schools > Dentistry Schools > Medicine
Publisher:	American Society for Microbiology
ISSN:	2150-7511
Date of First Compliant Deposit:	6 January 2026
Date of Acceptance:	2 December 2025
Last Modified:	06 Jan 2026 10:26
URI:	https://orca.cardiff.ac.uk/id/eprint/183575

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