A polytherapy based approach to combat antimicrobial resistance using cubosomes

Xiangfeng Lai, Mei-Ling Han, Yue Ding, Seong Hoong Chow, Anton P. Brun, Chun-Ming Wu, Phillip J. Bergen, Jhih-hang Jiang, Hsien-Yi Hsu, Benjamin W. Muir, Jacinta White, Jiangning Song, Jian Li () and Hsin-Hui Shen ()
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Xiangfeng Lai: Monash University
Mei-Ling Han: Monash University
Yue Ding: Monash University
Seong Hoong Chow: Monash University
Anton P. Brun: Australian Nuclear Science and Technology Organisation
Chun-Ming Wu: Australian Nuclear Science and Technology Organisation
Phillip J. Bergen: Monash University
Jhih-hang Jiang: Monash University
Hsien-Yi Hsu: City University of Hong Kong
Benjamin W. Muir: CSIRO Manufacturing
Jacinta White: CSIRO Manufacturing
Jiangning Song: Monash University
Jian Li: Monash University
Hsin-Hui Shen: Monash University

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract 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”.

Date: 2022
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DOI: 10.1038/s41467-022-28012-5

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