Nuclear techniques reveal membrane interaction for new therapeutic option to fight superbugs

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ANSTO has contributed to the search for a new therapeutic option to fight against antimicrobial resistant Gram-negative bacteria, called superbugs.

Research led by Professor Jian Li of Monash Biomedical Discovery Institute and Dr Hsin-Hui Shen of Monash’s Department of Biomedical Engineering has found an approach that could be an alternative when bacteria are resistant to current ‘last line of defense’ antibiotics. “.

The study published in Nature Communication by a broad collaboration of Australian, Taiwanese and Chinese scientists tackles a global health threat caused by the misuse and overuse of antimicrobials against pathogens.

Using a combination of techniques, the team found that using cubosomes (nanocarriers) loosely mixed with the antibiotic polymyxin showed promise for penetrating the bacteria’s impermeable outer membrane to reach the target.

In experiments, cubosomes were tested as a vehicle to deliver polymyxin, but the approach was less efficient than polymixing.

The interaction of antibiotics with Gram-negative bacteria. Reprinted under Creative Commons license http://creativecommons.org/licenses/by/4.0/. of Nature Communication https://doi.org/10.1038/s41467-022-28012-5

IThis is believed to be the first study to investigate bacterial killing using a combination of antibiotic combination therapy and nanoparticle carriers against Gram-negative pathogens.

Dr Anton Le Brun, instrument specialist at ANSTO’s Australian Neutron Scattering Center and co-author, assisted in the analysis using the Platypus neutron reflectometer to probe what was happening during the membrane interaction at the molecular level.

“This type of antibiotic is only effective against gram-negative bacteria because they target a specific molecule in the outer membrane,” said Dr. Le Brun, who has a long-standing antibiotic research collaboration with the Dr Shen.

However, there have been some reports of polymyxin resistance worldwide, with few new antibiotics in development.

Measurements using Platypus suggested that polymyxin initially interacted with the outer leaflet of the outer membrane, destabilizing the area. This activity allowed the cubosomes to come into contact with the bilayer, causing further disruption of the membrane.

“We fabricated an artificial surface that mimicked the properties of a bacterial cell surface,” explained Dr. Le Brun.

When the drug was encapsulated in the cubosome, it bound to the membrane but was not as efficient at crossing the barrier.

In previous work, the team found that cubosomes, liquid crystalline nanoparticles with properties suitable for use in drug delivery, had antimicrobial properties.

“For a long time, nanoparticles have been used as antimicrobial carriers,” Dr. Shen said.

“We found that the use of nanoparticle-antibiotic combination therapy can reduce dose delivery in the human body and overcome multi-drug resistance.”

First author Xiangfeng Lai is a doctoral candidate at Monash University.

In addition to Monash and ANSTO, collaborators included the National Center for Synchrotron Radiation Research (Taiwan), the Shenzhen Research Institute of the City University of Hong Kong, and CSIRO.

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