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A Polytherapy Based Approach to Combat Antimicrobial Resistance Using Cubosomes
X. Lai, M.-L. Han, Y. Ding, S. H. Chow, A. P. Le Brun, C.-M. Wu(吳浚銘), P. J. Bergen, J.-H. Jiang, H.-Y. Hsu, B. W. Muir, J. White, J. Song, J. Li*, and H.-H. Shen*
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”.