A team of Spanish synthetic biology scientists have created a ‘living pill’ that works against bacteria resistant to antibiotics and can fight lung infections that do not respond to these drugs. In a study to test this new treatment, it has been found to reduce acute lung infections in mice and double the survival rate.
This novel treatment has succeeded in dissolving the biofilms that accumulate on the surface of the endotracheal tubes of patients with ventilator-associated pneumonia, which is the leading cause of mortality in intensive care units. The mechanism of action of the live pill is to open holes in cell walls so that antibiotics can be introduced through them and eliminate infections at their source.
The results of the study have been published in Nature Biotechnology and open up new possibilities for the development of different strains of the ‘living pill’ that are useful in the treatment of other types of diseases of the respiratory system, such as lung cancer, asthma or pulmonary fibrosis. Its creators also design new proteins that can be delivered by the ‘living pill’.
Fight infections caused by ‘P. aeruginosa’
The first ‘living pill’ for the treatment of lung infections has been designed by a group of researchers from the Center for Genomic Regulation (CRG) and Pulmobiotics and is intended to combat Pseudomonas aeruginosa, a bacterium that presents a natural resistance to different types of antibiotics and is usually responsible for hospital infections.
“We have developed a battering ram that attacks antibiotic-resistant bacteria. We believe it is a promising new strategy to address the leading cause of hospital mortality.”
P. aeruginosa bacteria live in communities that form biofilms that can adhere to body surfaces and form structures that are beyond the reach of antibiotics. These biofilms grow, for example, on the surface of endotracheal tubes used by critically ill patients who need mechanical ventilators to breathe, causing ventilator-associated pneumonia (VAP). This condition can affect one in four (9-27%) patients who require intubation and the incidence exceeds 50% in the case of patients intubated due to severe COVID-19. VAP can also prolong the stay in the intensive care unit by up to 13 days, and its mortality rate is one in eight patients (9-13%).
How is the treatment with the ‘living pill’
To design the treatment, the researchers have used a modified version of the Mycoplasma pneumoniae bacterium, eliminating its pathogenic capacity and adapting it to attack P. aeruginosa, and have combined this modified bacterium with low doses of antibiotics that by themselves would not be effective against the infection.
When they administered the treatment to the mice, they found that the ‘living pill’ significantly reduced lung infections and doubled the survival rate of the animals compared to giving them no treatment at all. No signs of lung toxicity were observed with a single high dose of the treatment. After the end of the treatment, the innate immune system eliminated the modified bacteria in a period of four days.
M. pneumoniae is one of the smallest known species of bacteria, and the group of scientists modified it to dissolve biofilms, giving it the ability to produce several molecules, including pyocins, toxins that bacteria produce to kill or inhibit growth. of various strains of Pseudomonas. They collected P. aeruginosa biofilms from the endotracheal tubes of patients admitted to intensive care units and found that the treatment crossed the barrier and effectively dissolved the biofilms.
“We have developed a battering ram that attacks antibiotic-resistant bacteria. The treatment opens holes in cell walls and creates key entry points for antibiotics to invade and kill the infection at its source. We believe that it is a promising new strategy to address the main cause of hospital mortality”, says Dr. María Lluch, scientific director of Pulmobiotics, co-lead author of the study and researcher at the International University of Catalonia.
Dr. Luis Serrano, a specialist in synthetic biology and director of the CRG, had the idea of modifying M. pneumoniae and using it as a ‘living pill’ two decades ago. One of the advantages of this bacterium for treating respiratory diseases is that it is naturally adapted to lung tissue, so when the modified bacterium is administered it goes directly to the source of a respiratory infection, where it establishes itself as a temporary factory and produces various molecules. therapeutic.
The researchers are going to carry out new tests with the ‘living pill’ before reaching the clinical trial phase with the aim of using it to treat VAP. The treatment is expected to be delivered using a nebulizer, a device that turns liquid drug into a mist that is inhaled through a mouthpiece or mask.
The research has been led by the Center for Genomic Regulation (CRG) and Pulmobiotics in collaboration with the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), the Hospital Clínic de Barcelona and the Institute of Agrobiotechnology (IdAB), an institute for research by the CSIC and the government of Navarra, and has had the support of the “la Caixa” Foundation through the CaixaResearchHealth call.
Therapeutic cytokines to treat asthma or lung cancer
M. pneumoniae could also be used to treat other respiratory diseases such as lung cancer or asthma. “The bacterium can be modified with a variety of different active payloads, be they cytokines, nanobodies or defensins. The objective is to diversify the arsenal of the modified bacterium and unleash its potential in the treatment of a variety of complex diseases”, stated Dr. Serrano.
In fact, Dr. Serrano’s laboratory is working on the design of new proteins that can be administered by M. pneumoniae; Specifically, the team is using these proteins to combat inflammation caused by P. aeruginosa infections. Inflammation is the body’s response to infection, but if the inflammation is excessive or lasts for a long time, it can damage lung tissue.
The immune system triggers the inflammatory response by releasing mediator proteins such as cytokines, such as IL-10. Dr. Serrano’s research group has created new versions of IL-10 with properties that improve the treatment of inflammation. The scientific team has designed strains of M. pneumoniae that express these new cytokines and have tested their efficacy in the lungs of mice with acute P. aeruginosa infections. Engineered versions of IL-10 have been shown to be significantly more effective in reducing inflammation compared to the natural cytokine IL-10, according to the results of a study published in Molecular Systems Biology.
Ariadna Montero Blay, co-lead author of the aforementioned study, has pointed out that “biotherapeutic solutions such as M. pneumoniae provide ideal vehicles to overcome the traditional limitations of cytokines and unlock their enormous potential in the treatment of a variety of human diseases. The engineering of cytokines as therapeutic molecules was essential to combat inflammation. Other lung diseases such as asthma or pulmonary fibrosis could also benefit from this approach.”
Source: Center for Genomic Regulation (CRG)
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