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    A polytherapy based approach to combat antimicrobial resistance using cubosomes

    Year: 2022

    Journal: Nat. Commun., Volume 13, JAN 17

    Authors: Lai, Xiangfeng; Han, Mei-Ling; Ding, Yue; Chow, Seong Hoong; Le Brun, Anton P.; Wu, Chun-Ming; Bergen, Phillip J.; Jiang, Jhih-hang; Hsu, Hsien-Yi; Muir, Benjamin W.; White, Jacinta; Song, Jiangning; Li, Jian; Shen, Hsin-Hui

    Organizations: Australian NHMRC [GNT1106798]; NHMRC [APP1144652, APP1157909]

    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. An increasing prevalence of Gram-negative bacteria increases the interest in nanotherapies to treat antibiotic resistance. Here, the authors examine the antimicrobial activity of polymyxin-loaded cubosomes and explore a polytherapy treatment of pathogens with cubosomes in combination with polymyxin.
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