New organic molecule could become potent weapon in the fight against antibiotic resistance

An organic molecule composed of simple sugars could become a potent weapon in the fight against rising antibiotic resistance, according to EU-funded researchers who have developed a novel, targeted drug-delivery technique to treat deadly tuberculosis and other lethal pathogens.

The EU-funded CYCLON HIT project investigated cyclodextrins – cyclic oligosaccharides whose molecular composition is similar to common table sugar – as a nanotechnology-engineered carrier for antibiotics and other drugs. They discovered that cyclodextrin nanocarriers can be developed not only to efficiently encapsulate and protect antibiotics to combat resistant bacteria, but that these molecules also possess unique antimicrobial properties of their own.

We adopted a totally innovative approach in which cyclodextrins are not just used as nanocarriers of drug combinations but they also play an active role in fighting infection by interfering with the mechanism through which bacteria invade cells."

Ruxandra Gref, project coordinator, Centre National de la Recherche Scientifique in France

Targeting tuberculosis, one of the leading causes of death worldwide which claims more than 1.5 million lives each year, the CYCLON HIT team investigated a method to deliver antibiotic-enhanced cyclodextrin nanoparticles directly into the lungs, where the Mycobacterium tuberculosis pathogen accumulates in humans. This highly specialised bacteria uses part of the membrane of cells called lipid rafts to enter lung tissue where it is able to take up residence inside defensive cells known as macrophages, effectively hiding itself within the body’s own immune system.

‘Using this ingenious mechanism, the pathogen invades and persists inside macrophages despite their role in killing foreign bodies. We found that engineered cyclodextrins also preferentially locate at lipid rafts and act as a shield against pathogen penetration without any toxicity for the body,’ Gref says.

Cyclodextrins can therefore be engineered to perform two life-saving functions: preventing pathogens from invading cells, and delivering antibiotics and other medications to infected cells, providing a potent dual-action weapon against disease.

More targeted treatment, fewer side effects

Furthermore, a patented nanoparticle developed by the CYCLON HIT researchers made from β-cyclodextrin nanoparticles could enable the administration of antibiotic drug combinations directly into the lungs via an inhaler rather than patients having to ingest slow-acting and less-effective pills.

Following the failure of first-line antibiotics, multidrug-resistant tuberculosis is currently treated with chemotherapy or second-line antibiotics such as ethionamide in combination with other drugs. But patients often find it difficult to comply with treatment regimens that can require taking more than 10 000 tablets over a two-year period, frequently with debilitating side effects.

‘The engineered cyclodextrins were able to incorporate antibiotics, preserving their activity and delivering them safely to the infected cells,’ Gref says. ‘Tests in animal models show that this approach achieves higher drug concentrations at the target site and less systemic side effects for the patient.’

While multidrug-resistant tuberculosis was a key test case for the CYCLON HIT researchers, their engineered cyclodextrin nanocarriers also have the potential to be deployed against a range of other pathogens, such as Salmonella typhimurium, responsible for severe gastroenteritis; Staphyloccocus aureus, an opportunistic pathogen linked to skin infections and respiratory infections; and the types of gram-negative bacteria most commonly implicated in hospital infections.

Given that all species of bacteria are continuously mutating in response to the selective pressure of antibiotics, leading to multidrug resistance and potentially untreatable disease, sustained research efforts are needed to develop novel ways of delivering effective treatments.

To that end, the CYCLON HIT project has laid the foundations for ongoing research into the vast potential of cyclodextrins through a training programme for 11 early-stage and five young experienced researchers, supported by the interdisciplinary expertise of 12 research institutes and innovative SMEs across Europe.

Gref says collaborations are continuing on several fronts beyond the end of the Marie-Curie Initial Training Networks project, with members of the project consortium currently seeking partnerships with companies to further develop and commercialize the nanotechnology.