Ultrasound-activated ‘nanoagents’ kill superbugs hiding in biofilms

Delivering antibiotics locally, directly to the site of an infection, is important, because treating the whole body with high doses increases the chances of bacteria developing resistance. Nanoagents can carry drugs straight to the infected area providing localised therapy with minimal amount of drug, reducing the risks of antibiotic resistance.

Publishing their findings in JACS Au, researchers from the University of Birmingham and Nottingham Trent University reveal the results of designing the particles so they can hide an antibiotic, rifampicin, in their interior and testing their antibacterial activity when ultrasound is applied. An antimicrobial drug, rifampicin is used to treat tuberculosis and Staphylococcus aureus infections, including those associated with medical implants.

Many bacterial infections form biofilms - sticky, protective layers that make them very hard to treat. Biofilms cause a lot of infections and resist many antibiotics because the drugs cannot easily penetrate their thick structure. Water repelling antibiotics like rifampicin are especially ineffective because they struggle to get deep inside these moist, gel like biofilms.

In their studies the researchers show that low frequency ultrasound not only helps the nanoparticles to move deeper into the biofilm but also causes tiny bubbles that shake the drug loose from the particles at just the right time.

Professor Zoe Pikramenou, from the University of Birmingham, said: “We found that these nanoparticles are only activated with ultrasound to release the drug and they kill bacteria in biofilms far better than rifampicin alone, as they travel through all the layers of the biofilm.”

“The particles are biocompatible and showed low toxicity to human epithelial cells, suggesting strong potential for future medical use. We’ve found a new way to deliver difficult antibiotics more effectively, using an approach that could be adapted for other hard-to-deliver drugs, potentially including cancer therapies.”

Dr Sarah Kuehne, Associate Professor of Microbiology in Nottingham Trent University’s School of Science and Technology, said “Deploying such particles may mean that lower doses of the drug are needed, reducing the risk of antibiotic resistance and unwanted side-effects.

“Biofilm infections are common in wounds, , implants, and medical devices but hard to treat. This approach allows hard-to-reach areas to be treated.”

Staphylococcus aureus biofilms treated with nanoparticles combined with ultrasound killed 90% of the biofilm. Without ultrasound they achieved only 20 % reduction, while treatment with free rifampicin and LFUS resulted only in a 10 % reduction. Without ultrasound, the nanoparticles only reached the top 1.6μm of the biofilm, but with ultrasound they reached about 5.6μm, nearly the entire thickness.

The nanoagents are tiny silica particles designed with a water repelling inner core to hold the drug and a ‘water-loving’ outer shell so that they remain stable in biological environments. Researchers also made a fluorescent version of the particles by adding dye so they could track them inside the biofilms, supporting the localised delivery of the drug and penetration depth.

An excellent team of early career researchers supported the studies drawing expertise from nanoparticles, ultrasound, microbiology and solid state particle characterisation. The project was funded by EPSRC, “SONATA” grant led by Zoe Pikramenou, Damien Walmsley, and Sarah Kuehne.

Professor Pikramenou leads a nanochemistry group at the University of Birmingham. The team runs a broad range of research projects based on light-activated nanoparticles for detection and localised therapies.