Synthetic biology offers new strategies to address leading cause of death in hospitals
Researchers have designed the first ‘living medicine’ to treat lung infections. The treatment targets Pseudomonas aeruginosa, a type of bacteria that is naturally resistant to many types of antibiotics and is a common source of hospital infections.
This treatment involves using a modified version of the Mycoplasma pneumoniae bacterium to remove its disease-causing ability and instead repurpose it to attack Pseudomonas aeruginosa. The modified bacteria are used in combination with low-dose antibiotics that would otherwise not work alone.
Researchers tested the efficacy of the treatment in mice and found a significant reduction in lung infections. The ‘herbal medicine’ doubled the survival rate of the mice compared to no treatment. A single high-dose treatment showed no signs of pulmonary toxicity. Once treatment was complete, her innate immune system eliminated the modified bacteria in four days.
Findings are published in the journal nature biotechnology It is also supported by the ‘la Caixa’ foundation through the CaixaResearch Health call. The study was led by researchers from the Center for Genomic Regulation (CRG) and Pulmobiotics, with the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), the Hospital Clinic de Barcelona, and the Institute of Agrobiotechnology (IdAB) in collaboration. done collaboratively. CSIC Institute in Spain and the Government of Navarre.
Pseudomonas aeruginosa infections are difficult to treat because the bacteria live in biofilm-forming communities. Biofilms adhere to various surfaces in the body and form impenetrable structures that are impenetrable to antibiotics.
Pseudomonas aeruginosa biofilms can grow on the surface of endotracheal tubes used by critically ill patients who require mechanical ventilation for breathing. This causes ventilator-associated pneumonia (VAP). It is a condition that affects her 1 in 4 (9–27%) of patients who require intubation. The incidence of patients intubated due to severe Covid-19 exceeds 50%. VAP can prolong the length of stay in the intensive care unit by up to 13 days and kill 1 in 8 (9–13%) patients.
The authors of this study suggest that M. lyses biofilms by possessing the ability to produce various molecules, including pyocins, toxins naturally produced by bacteria to kill or inhibit the growth of Pseudomonas strains. I manipulated . pneumoniae. To test its efficacy, they collected Pseudomonas aeruginosa biofilms from endotracheal tubes of intensive care unit patients. They found that the treatment penetrated the barrier and successfully dissolved the biofilm.
“We have developed a battering ram that surrounds antibiotic-resistant bacteria. This treatment punctures the cell wall, providing a critical gateway for antibiotics to enter and clear the source of infection.” We believe this is a promising new strategy to address a leading cause of death in hospitals,” said Pulmobiotics chief scientific officer and co-corresponding author of the study, Catalonia said Dr. María Lluch, principal investigator at the International University of Japan.
With the aim of using a “living drug” to treat VAP, researchers will conduct further trials before it reaches the clinical trial stage. Treatment using a device called a “nebulizer” is expected.
M. pneumoniae is one of the smallest known bacterial species. Dr. Luis Serrano, director of the CRG, first came up with the idea of modifying bacteria to be used as a ‘living medicine’ 20 years ago. Dr. Serrano is an expert in synthetic biology. Synthetic biology is a field that involves reusing organisms and engineering them to have new and useful abilities. With only 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 disease is its natural adaptation to lung tissue. After administering the modified bacterium, it goes straight to the source of the respiratory infection, where it sets up a temporary factory-like factory to produce various therapeutic molecules.
By showing that M. pneumoniae can fight lung infections, this study paves the way for researchers to create new bacterial strains to tackle other types of respiratory diseases, such as lung cancer and asthma. “Bacteria can be modified with different payloads, including cytokines, nanobodies and defensins. ,” said Dr. Luis Serrano, a research professor at ICREA.
In addition to designing “living medicines,” Dr. Serrano’s research team is drawing on its expertise in synthetic biology to design novel proteins delivered by pneumococci. The team is using these proteins to target inflammation caused by Pseudomonas aeruginosa infection.
Inflammation is the body’s natural response to infection, but excessive or prolonged inflammation can damage lung tissue. The inflammatory response is coordinated by the immune system releasing mediator proteins such as cytokines. IL-10, a cytokine, has well-known anti-inflammatory properties and is of increasing therapeutic interest.
In a study published in Molecular Systems Biology, Dr. Serrano’s research group used the protein design software ModelX and FoldX to design a new version of IL-10 that was intentionally optimized to treat inflammation. . Cytokines are designed to be made more efficiently and have higher affinity. That means less cytokines are needed to get the same effect.
Researchers engineered a new cytokine-expressing strain of pneumococcus and tested its efficacy in the lungs of mice with acute Pseudomonas aeruginosa infection. They found that engineered versions of IL-10 were significantly more effective in reducing inflammation compared to wild-type IL-10 cytokines.
According to Ariadna Montero Blay, Ph.D., co-author of the study in Molecular Systems Biology, “Live biotherapeutics such as M. pneumoniae overcome the traditional limitations of cytokines and unlock enormous potential in a variety of human therapeutics. It provides an ideal vehicle for disease.Manipulation of cytokines as therapeutic molecules has been important for tackling inflammation.Other lung diseases such as asthma and pulmonary fibrosis could also benefit from this approach. there is potential.”
Original: A ‘living medicine’ created to combat drug-resistant lung infections
Than: Center for Genome Regulation | Spanish National Research Council | | Higher Institute of Catalan Studies
