Repurposed anticancer agent becomes sound-activated antibacterial drug candidate

A sound-activated antibacterial offers a promising alternative to conventional antibiotics for deep-tissue bacterial infections. Upon exposure to ultrasound, the sono-sensitive ruthenium complex generates reactive oxygen species that can damage bacterial DNA and biofilms without triggering the evolution of resistance. The team behind the work believes that this blend of general mechanism and localised effect provides a powerful framework for treatments that could beat antibiotic-resistant microorganisms.

Antimicrobial resistance is a significant global health problem, with deaths from drug-resistant infections expected to exceed cancer by 2050. Consequently, there is an urgent need to develop treatments that are less vulnerable to these evolved defensive pathways and, in recent years, stimuli-responsive therapies have emerged as a promising option. ‘We administer a compound, which itself is non-toxic, and then use an external trigger such as light or ultrasound to generate reactive oxygen species that then damage the bacteria,’ explains Johannes Karges, a medicinal inorganic chemist at Ruhr University Bochum who wasn’t involved in the new work. ‘It’s only where the two come together that you have an effect, and this can be very strongly controlled by a doctor.’

Photodynamic therapy using light is already well-established for treating skin infections and cancers but the limited penetration of safe light wavelengths restricts this approach. Conversely, ultrasound can penetrate much deeper into tissues, but localising sufficient sensitiser around infection sites has proven challenging and these agents are therefore comparatively underdeveloped.

However, using a DNA-targeting scaffold previously developed as an anticancer photodynamic therapy drug, the Chinese and Korean team were able to direct a ruthenium-based sono-sensitiser exclusively towards infected lung tissue. Unlike animal cells, where genetic information is enclosed within a membrane-bound nucleus, bacterial DNA is free-floating within the cytoplasm, making it an accessible target for small molecule drugs. The ruthenium complex TLD1433 therefore rapidly concentrates around the site of infection, meaning subsequent activation with ultrasound focuses oxidative damage on bacteria rather than healthy cells. This switch in activation mechanism to more penetrating ultrasound also provides access to deeper tissues, previously unreachable with light, expanding the potential of this treatment approach,  the team says.

In a direct in vitro comparison, TLD1433 outperformed both a conventional antibiotic (ciprofloxacin) and a standard sono-sensitiser against pneumonia pathogens, reducing bacterial survival to just 14% and even relieving the hypoxic environment created by the bacterial biofilm. These promising results were further confirmed by the team’s mouse studies: all mice survived when treated with TLD1433 plus ultrasound, versus just a quarter of the control group.

‘I think this is a very strong proof-of-concept that we can use other classes of compound with established properties for sono-dynamic applications,’ says Karges. A big strength, he notes, is that TLD1433 is currently in phase 2 clinical trials as a photosensitiser, meaning the biosafety and pharmacokinetic properties are already well-optimised.

More broadly though, the work presents encouraging evidence for sono-dynamic therapy as one solution against antimicrobial resistance. ‘The sensitiser is interacting with the whole environment so it’s very hard for bacteria to develop resistance against. That’s a big advantage over antibiotics,’ Karges says.