This reveals a cross-section of a mouse lung contaminated with Pseudonomas aeruginosa. The mouse was handled with a model of Mycoplasma pneumoniae that would not produce therapeutic molecules, leading to extreme pneumoniae. This is characterised by large infiltration of inflammatory cells into the alveolar septa, leading to lack of air within the alveoli. Credit: Rocco Mazzolini/CRG
Synthetic biology presents novel approaches to fight the first reason for loss of life in hospitals.
Scientists have created the primary “living medicine” to treatment lung infections. This modern remedy is geared toward Pseudomonas aeruginosa, a micro organism recognized for its resistance to many antibiotics and a frequent reason for infections in hospitals.
This remedy entails the usage of a modified type of the Mycoplasma pneumoniae bacterium, which has had its disease-causing skills eliminated and reprogrammed to focus on P. aeruginosa. The modified bacterium is used along with low doses of antibiotics that will not be efficient on their very own.
Researchers examined the efficacy of the remedy in mice, discovering that it considerably diminished lung infections. The “living medicine” doubled mouse survival fee in comparison with not utilizing any remedy. Administering a single, excessive dose of the remedy confirmed no indicators of toxicity within the lungs. Once the remedy had completed its course, the innate immune system cleared the modified micro organism in a interval of 4 days.
The findings are revealed within the journal Nature Biotechnology and had been funded by the “la Caixa” Foundation by the CaixaResearch Health name. The research was led by researchers on the Centre for Genomic Regulation (CRG) and Pulmobiotics in collaboration with the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic de Barcelona and the Institute of Agrobiotechnology (IdAB), a joint analysis institute of Spain’s CSIC and the federal government of Navarre.
This reveals a cross-section of a mouse lung contaminated with Pseudonomas aeruginosa. The mouse was handled with a model of Mycoplasma pneumoniae that is ready to produce therapeutic molecules equivalent to pyocins particularly designed to fight P. aeruginosa. This therapeutic model of M. pneumoniae acts like a ‘living medicine’ lowering the consequences of the an infection and preserving air within the alveoli. Credit: Rocco Mazzolini/CRG
P. aeruginosa infections are troublesome to deal with as a result of the micro organism reside in communities that kind biofilms. Biofilms can connect themselves to numerous surfaces within the physique, forming impenetrable constructions that escape the attain of antibiotics.
P. aeruginosa biofilms can develop on the floor of endotracheal tubes utilized by critically-ill sufferers who require mechanical ventilators to breathe. This causes ventilator-associated pneumonia (VAP), a situation that impacts one in 4 (9-27%) sufferers who require intubation. The incidence exceeds 50% for sufferers intubated due to extreme Covid-19. VAP can lengthen the period within the intensive care unit for as much as 13 days and kills as much as one in eight sufferers (9-13%).
The authors of the research engineered M. pneumoniae to dissolve biofilms by equipping it with the flexibility to provide varied molecules together with pyocins, toxins naturally produced by micro organism to kill or inhibit the expansion Pseudomonas bacterial strains. To take a look at its efficacy, they collected P. aeruginosa biofilms from the endotracheal tubes of sufferers in intensive care models. They discovered the remedy penetrated the barrier and efficiently dissolved the biofilms.
“We have developed a battering ram that lays siege to antibiotic-resistant bacteria. The treatment punches holes in their cell walls, providing crucial entry points for antibiotics to invade and clear infections at their source. We believe this is a promising new strategy to address the leading cause of mortality in hospitals,” says Dr. María Lluch, Chief Scientific Officer at Pulmobiotics, co-corresponding creator of the research and principal investigator on the International University of Catalonia.
With the intention of utilizing “living medicine” to deal with VAP, the researchers will perform additional checks earlier than reaching the medical trial part. The remedy is anticipated to be administered utilizing a nebulizer, a system that turns liquid drugs right into a mist which is then inhaled by a mouthpiece or a masks.
M. pneumoniae is likely one of the smallest recognized species of bacteria. Dr. Luis Serrano, Director of the CRG, first had the idea to modify the bacteria and use it as a ‘living medicine’ two decades ago. Dr. Serrano is a specialist in synthetic biology, a field that involves repurposing organisms and engineering them to have new, useful abilities. With just 684 genes and no cell wall, the relative simplicity of M. pneumoniae makes it ideal for engineering biology for specific applications.
One of the advantages of using M. pneumoniae to treat respiratory diseases is that it is naturally adapted to lung tissue. After administering the modified bacterium, it travels straight to the source of a respiratory infection, where it sets up shop like a temporary factory and produces a variety of therapeutic molecules.
By showing that M. pneumoniae can tackle infections in the lung, the study opens the door for researchers to create new strains of the bacteria to tackle other types of respiratory 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,” says ICREA Research Professor Dr. Luis Serrano.
In addition to designing the ‘living medicine’, Dr. Serrano’s research team is also using their expertise in synthetic biology to design new proteins that can be delivered by M. pneumoniae. The team is using these proteins to target inflammation caused by P. aeruginosa infections.
Though inflammation is the body’s natural response to an infection, excessive or prolonged inflammation can damage lung tissue. The inflammatory response is orchestrated by the immune system, which releases mediator proteins such as cytokines. One type of cytokine – IL-10 – has well-known anti-inflammatory properties and is of growing therapeutic interest.
Research published in the journal Molecular Systems Biology by Dr. Serrano’s research group used protein-design softwares ModelX and FoldX to engineer 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, meaning less cytokines are needed to have the same effect.
The researchers engineered strains of M. pneumoniae that expressed the new cytokines and tested its efficacy in the lungs of mice with acute P. aeruginosa infections. They found that engineered versions of IL-10 were significantly more effective at reducing inflammation compared to the wild-type IL-10 cytokine.
According to Dr. Ariadna Montero Blay, co-corresponding author of the study in Molecular Systems Biology, “live biotherapeutics such as M. pneumoniae provide ideal vehicles to help overcome the traditional limitations of cytokines and unlock their huge potential in treating a variety of human diseases. Engineering cytokines as therapeutic molecules was critical to tackle inflammation. Other lung diseases such as asthma or pulmonary fibrosis could also stand to benefit from this approach.”
Reference: “Engineered live bacteria suppress Pseudomonas aeruginosa infection in mouse lung and dissolve endotracheal-tube biofilms” by Rocco Mazzolini, Irene Rodríguez-Arce, Laia Fernández-Barat, Carlos Piñero-Lambea, Victoria Garrido, Agustín Rebollada-Merino, Anna Motos, Antoni Torres, Maria Jesús Grilló, Luis Serrano and Maria Lluch-Senar, 19 January 2023, Nature Biotechnology.
DOI: 10.1038/s41587-022-01584-9
