Study Shows Modified Bacteria Can Tackle Drug-resistant Lung Infection

A cross-section of a mouse lung infected with Pseudonomas aeruginosa. The mouse was treated with a version of Mycoplasma pneumoniae that is able to produce therapeutic molecules. Credit: Rocco Mazzolini/CRG

Ventilator-associated pneumonia, an infection caused by the multi-drug resistant bacteria Pseudomonas aeruginosa, typically affects 1-in-4 critically ill patients who require intubation. However, that percentage soared for intubated patients with severe COVID-19, exceeding 50 percent.

P. aeruginosa infections are difficult to treat because the bacteria live in communities that form biofilms. The biofilms attach themselves to the surface of endotracheal tubes used by ventilator-assisted patients, forming impenetrable structures that escape the reach of antibiotics. Ventilator-associated pneumonia (VAP) can extend a patient’s duration in ICU for up to 13 days, and kills up to 13 percent of patients.

Now, researchers from the Center for Genomic Regulation have designed the first “living medicine” to treat infections caused by P. aeruginosa. The treatment involves using a modified version of the bacterium Mycoplasma pneumoniae, repurposing it to attack P. aeruginosa. The bacterium is then used in combination with low doses of the same antibiotics that P. aeruginosa is normally resistant to.

For the study, published in Nature Biotechnology, the team equipped M. pneumoniae with the ability to produce various molecules to kill the biofilms, including pyocins, or toxins naturally produced by bacteria to kill or inhibit the growth of strains.

To test the “living medicine,” the team collected P. aeruginosa biofilms from the endotracheal tubes of 16 patients in intensive care units. They then administered the treatment to mice. According to the study results, the M. pneumoniae-derived medicine doubled mouse survival rate compared with controls using no treatment.

Additionally, the researchers found that a single, high dose of the treatment showed no signs of toxicity in the lungs. Once the treatment had finished its course, the innate immune system cleared the modified bacteria in four days.

“We have developed a battering ram that lays siege to antibiotic-resistant bacteria,” said co-corresponding author of the study María Lluch, Chief Scientific Officer at Pulmobiotics. “The treatment punches holes in their cell walls, providing crucial entry points for antibiotics to invade and clear infections at their source.”

With just 684 genes and no cell wall, the researchers say M. pneumoniae holds significant advantages over other bacteria, making it ideal for engineering biology—specifically respiratory infections. For example, in the latest study, modified M. pneumoniae was shown to travel straight to the source of the lung infection—where it quickly and efficiently produced a variety of therapeutic molecules.

But lung infections are not the only type of respiratory infections. Luckily, the scientists say M. pneumoniae’s demonstrated success in the lung opens the door for other diseases, such as lung cancer or asthma.

“The bacterium can be modified with a variety of different payloads—whether these are cytokines, nanobodies or defensins. The aim is to diversify the modified bacterium’s arsenal and unlock its full potential in treating a variety of complex diseases,” said Luis Serrano, research professor at the Catalan Institution for Research and Advanced Studies in Spain.

In addition to the “living medicine,” Serrano and his team used their M. pneumoniae expertise to design new proteins that can be delivered by the bacteria. They are currently using these proteins to target inflammation caused by P. aeruginosa infections.