Inhaled living medicine reduces drug-resistant lung biofilms in the lungs of pigs

A "living medicine" has thinned biofilms of antibiotic-resistant Pseudomonas aeruginosa in the lungs of pigs, according to the findings of a study published today in the journal eBioMedicine.

The experimental treatment involves inhaling a genetically modified bacterium designed to target layers of drug-resistant P. aeruginosa that grow on the surfaces of endotracheal tubes used in hospitals.

It's the first time the experimental treatment, which has previously only been shown to tackle biofilms in mice, has also worked in pigs, a large animal with lungs that are similar in size, structure and immune response to human lungs.

It's also the first time the treatment has been shown to be administrable through a nebulizer, the same type of medical device human patients would use. Breathing in the "living medicine" thinned the biofilm inside breathing tubes from 6.08 to 3.67 micrometres, reducing thickness by around 40%.

The treatment involves Mycoplasma pneumoniae, a bacterium which normally causes a mild lung infection but, through genetic engineering, has been repurposed to be harmless for humans. The engineered bacterium was loaded with genes that dissolve sugars holding a biofilm together, as well as toxins that specifically only target Pseudomonas aeruginosa.

Our study is part of an emerging field of medicine known as live biotherapeutics. In this case we've taken a bacterium naturally adapted to the lung and reprogrammed it so that it delivers therapeutic molecules instead of causing damage. It's a Trojan horse strategy against disease."

Dr. Irene Rodríguez-Arce, senior co-author of the study

When examining the lungs afterwards, there were no signs of damage caused by the engineered bacterium. The treatment also showed no measurable effect on the animals' own airway bacteria, suggesting the living medicine targets Pseudomonas specifically.

The study could one day help patients who cannot breathe for themselves in hospital. They are usually kept alive by passing a tube into the windpipe. Within days, bacteria colonise the inside of that tube and form slimy, protective layer called a biofilm.

Antibiotics given through a drip struggle to penetrate the physical barrier of biofilms, causing recurring infections. In intubated patients, this is a known cause of ventilator-associated pneumonia (VAP). Around 1 in 4 cases are caused by Pseudomonas aeruginosa, which is frequently resistant to several types of antibiotics.

"Antibiotic resistance is a silent pandemic we see affecting intubated patients every day and Pseudomonas aeruginosa is among the hardest infections to clear. Our work represents a different line of attack, and one we badly need," says Dr. Antoni Torres, senior co-author of the study.

The authors say their findings support a future first-in-human safety trial. Combining the "living medicine" with intravenous antibiotics or making make further tweaks to the molecules that dissolve biofilms could further improve the experimental treatment's effectiveness.

"I am confident that with modifications to the bacterial chassis' payload, we could completely dissolve the biofilms on the surface of endotracheal tubes and clear P. aureginosa infections entirely," explains ICREA Research Professor Luis Serrano, senior co-author of the study. The research team at the CRG are also creating versions of the living medicine that can tackle pulmonary fibrosis and lung cancer.

The study is a collaboration between the Centre for Genomic Regulation (CRG) and Hospital Clínic-IDIBAPS, both in Barcelona, with the animal studies carried out at the University of Barcelona. It was led by co first-authors Laia Fernández-Barat and Ana Motos, with Antoni Torres, Luis Serrano and Irene Rodríguez-Arce as senior authors. The study is funded by the "la Caixa" Foundation and the European Research Council.