This is a cross-section of a mouse lung infected with Pseudonomas aeruginosa. The mouse was given a medication that was unable to produce therapeutic compounds, leading to severe pneumoniae, which is characterized by a large infiltration of inflammatory cells into the alveolar septa, resulting in a loss of air in the alveoli.
Scientists have developed the first "living medicine" to treat lung infections. The aim of this innovative therapy is targeting Pseudomonas aeruginosa, a bacteria that is well-known for its resistance to many antibiotics and is a frequent culprit of hospital infections.
This treatment involves the use of a modified Mycoplasma pneumoniae bacterium that has had its disease-causing abilities removed and reprogrammed to target P. aeruginosa. The modified bacterium is used alongside low doses of antibiotics that would not be effective on their own.
Researchers examined the effectiveness of the therapy in mice, finding that it significantly reduced lung infections. The "living medicine" doubled the survival rate of mice when administered only one dose of the medication. There were no signs of toxicity in the lungs when the treatment finished its dosage.
The findings have been published in the journal Nature Biotechnology, and were funded by the "la Caixa" foundation through the CaixaResearchHealth call. Researchers from the CRG, the Hospital Clinic of Barcelona, and the IdAB, a joint research institute, have conducted the study.
This is a cross-section of a mouse lung infected with Pseudonomas aeruginosa. This therapeutic version of M. pneumoniae is able to synthesize therapeutic substances, such as pyocins, specifically developed to combat P. aeruginosa.
Infections with P. aeruginosa are difficult to treat because the bacteria dwell in biofilms that attach themselves to various parts of the body, forming impenetrable structures that are beyond the reach of antibiotics.
Biofilms from P. aeruginosa may grow on the surface of endotracheal tubes used by critically-ill patients who require mechanical ventilators to breathe. This condition affects one out of every four (9-27%) patients who require intubation and a staggering half for patients who are intubated due to severe Covid-19.
The authors of the study crafted M. pneumoniae to break down biofilms by instilling various compounds including pyocins, bacteria's natural substances that kill or inhibit the growth of Pseudomonas bacterial strains. The treatment penetrated the barrier and successfully dissected the biofilms.
"We have developed a battering ram that sieges antibiotic-resistant bacteria," says Dr. Mara Lluch, the study's principal investigator at the International University of Catalonia.
Researchers will undertake additional research before entering the clinical testing phase. The treatment will be administered using a nebulizer, a device that turns liquid medicine into a mist, which is then inhaled through a mouthpiece or a mask.
M. pneumoniae is the smallest known bacteria. Dr. Luis Serrano, the director of the CRG, first proposed to modify the bacteria and make it a "living medicine" two decades ago. Dr. Serrano is a specialist in synthetic biology, a discipline that involves repurposing organisms and creating them to have new, useful abilities.
M. pneumoniae is naturally adapted to lung tissue, so it travels straight to the source of a respiratory illness, where it establishes a shop like a temporary factory, producing a variety of therapeutic compounds.
The discovery of M. pneumoniae's capability to treat lung infections opens the way for researchers to develop new strains to tackle other respiratory illnesses, such as lung cancer or asthma. The objective is to broaden the modified bacterium's arsenal and unlock its full potential in treating a variety of complex illnesses, according to ICREA Research Professor Dr. Luis Serrano.
Dr. Serrano's research group is also using their scientific expertise to develop new proteins that can be delivered by M. pneumoniae. The team is also focusing on the inflammation caused by P. aeruginosa infections.
Overuse or prolonged inflammation can damage lung tissue, as a result of the immune system's release of mediator proteins, such as cytokines. One type of cytokine – IL-10 – is well-known anti-inflammatory properties and is of growing therapeutic interest.
Dr. Serrano's research group used protein-design software ModelX and FoldX to create new versions of IL-10 purposefully optimized to treat inflammation. The cytokines were designed to be created more efficiently and to have a higher affinity, so less cytokines are required to have the same effect.
Researchers modified M. pneumoniae strains that expressed the new cytokines and tested their effectiveness in mice with acute P. aeruginosa infections. They found that engineered versions of IL-10 were significantly more effective at reducing inflammation than wild-type IL-10 cytokine.
According to Dr. Ariadna Montero Blay, the co-author of the study in Molecular Systems Biology, "live biotherapeutics such as M. pneumoniae are ideal vehicles to assist overcome the traditional limitations of cytokines and unlock their enormous potential in treating a wide spectrum of human illnesses."
"Engineered live bacteria suppress Pseudomonas aeruginosa infection in mouse lung and dissolve endotracheal-tube biofilms," by Rocco Mazzolini, Irene Rodrguez-Arce, Victoria Garrido, Agustn Rebollada-Merino, Anna Motos, Antoni Torres, Maria Jess Grilló, Luis Serrano, and Maria Lluch-Senar, 19 January