Browsing by Author "Muir, BW"

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    Polysaccharide‐targeting lipid nanoparticles to kill gram‐negative bacteria
    (Wiley, 2023-10-05) Lai, XF; Chow, SH; Le Brun, AP; Muir, BW; Bergen, PJ; White, JF; Yu, HH; Wang, JP; Danne, J; Jiang, JH; Short, FL; Han, ML; Strugnell, RA; Song, JN; Cameron, NR; Peleg, AY; Li, J; Shen, HH
    The rapid increase and spread of Gram‐negative bacteria resistant to many or all existing treatments threaten a return to the preantibiotic era. The presence of bacterial polysaccharides that impede the penetration of many antimicrobials and protect them from the innate immune system contributes to resistance and pathogenicity. No currently approved antibiotics target the polysaccharide regions of microbes. Here, describe monolaurin‐based niosomes, the first lipid nanoparticles that can eliminate bacterial polysaccharides from hypervirulent Klebsiella pneumoniae, are described. Their combination with polymyxin B shows no cytotoxicity in vitro and is highly effective in combating K. pneumoniae infection in vivo. Comprehensive mechanistic studies have revealed that antimicrobial activity proceeds via a multimodal mechanism. Initially, lipid nanoparticles disrupt polysaccharides, then outer and inner membranes are destabilized and destroyed by polymyxin B, resulting in synergistic cell lysis. This novel lipidic nanoparticle system shows tremendous promise as a highly effective antimicrobial treatment targeting multidrug‐resistant Gram‐negative pathogens. © 2023 The Authors. Published by Wiley-VCH GmbH2305052
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    A polytherapy based approach to combat antimicrobial resistance using cubosomes
    (Springer Nature, 2022-01-17) Lai, XF; Han, ML; Ding, Y; Chow, SH; Le Brun, AP; Wu, CM; Bergen, PJ; Jiang, JH; Hsu, HY; Muir, BW; White, J; Song, JN; Li, J; Shen, HH
    A depleted antimicrobial drug pipeline combined with an increasing prevalence of Gram-negative ‘superbugs’ has increased interest in nano therapies to treat antibiotic resistance. As cubosomes and polymyxins disrupt the outer membrane of Gram-negative bacteria via different mechanisms, we herein examine the antimicrobial activity of polymyxin-loaded cubosomes and explore an alternative strategy via the polytherapy treatment of pathogens with cubosomes in combination with polymyxin. The polytherapy treatment substantially increases antimicrobial activity compared to polymyxin B-loaded cubosomes or polymyxin and cubosomes alone. Confocal microscopy and neutron reflectometry suggest the superior polytherapy activity is achieved via a two-step process. Firstly, electrostatic interactions between polymyxin and lipid A initially destabilize the outer membrane. Subsequently, an influx of cubosomes results in further membrane disruption via a lipid exchange process. These findings demonstrate that nanoparticle-based polytherapy treatments may potentially serve as improved alternatives to the conventional use of drug-loaded lipid nanoparticles for the treatment of “superbugs”. © The Authors - Open Access CC-BY 4.0
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    A polytherapy based approach to combat antimicrobial resistance using cubosomes
    (Springer Nature, 2022-01-17) Lai, XF; Han, ML; Ding, Y; Chow, SH; Le Brun, AP; Wu, CM; Bergen, PJ; Jiang, JH; Hsu, HY; Muir, BW; White, J; Song, JN; Shen, HH
    A depleted antimicrobial drug pipeline combined with an increasing prevalence of Gram-negative ‘superbugs’ has increased interest in nano therapies to treat antibiotic resistance. As cubosomes and polymyxins disrupt the outer membrane of Gram-negative bacteria via different mechanisms, we herein examine the antimicrobial activity of polymyxin-loaded cubosomes and explore an alternative strategy via the polytherapy treatment of pathogens with cubosomes in combination with polymyxin. The polytherapy treatment substantially increases antimicrobial activity compared to polymyxin B-loaded cubosomes or polymyxin and cubosomes alone. Confocal microscopy and neutron reflectometry suggest the superior polytherapy activity is achieved via a two-step process. Firstly, electrostatic interactions between polymyxin and lipid A initially destabilize the outer membrane. Subsequently, an influx of cubosomes results in further membrane disruption via a lipid exchange process. These findings demonstrate that nanoparticle-based polytherapy treatments may potentially serve as improved alternatives to the conventional use of drug-loaded lipid nanoparticles for the treatment of “superbugs”. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International Licence.
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    An x-ray and neutron reflectometry study of 'PEG-like' plasma polymer films
    (The Royal Society, 2012-05-07) Menzies, DJ; Nelson, A; Shen, HH; McLean, KM; Forsythe, JS; Gengenbach, TR; Fong, C; Muir, BW
    Plasma-enhanced chemical vapour-deposited films of di(ethylene glycol) dimethyl ether were analysed by a combination of X-ray photoelectron spectroscopy, atomic force microscopy, quartz crystal microbalance with dissipation monitoring (QCM-D), X-ray and neutron reflectometry (NR). The combination of these techniques enabled a systematic study of the impact of plasma deposition conditions upon resulting film chemistry (empirical formula), mass densities, structure and water solvation, which has been correlated with the films' efficacy against protein fouling. All films were shown to contain substantially less hydrogen than the original monomer and absorb a vast amount of water, which correlated with their mass density profiles. A proportion of the plasma polymer hydrogen atoms were shown to be exchangeable, while QCM-D measurements were inaccurate in detecting associated water in lower power films that contained loosely bound material. The higher protein resistance of the films deposited at a low load power was attributed to its greater chemical and structural similarity to that of poly(ethylene glycol) graft surfaces. These studies demonstrate the utility of using X-ray and NR analysis techniques in furthering the understanding of the chemistry of these films and their interaction with water and proteins. Copyright © The Royal Society 2012.