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Genome-reduced ‘living medicine’ created for drug-resistant infections

Researchers from the Centre for Genomic Regulation have created a ‘living medicine’ to treat antibiotic-resistant bacteria growing on the surfaces of medical implants. The team created the treatment by engineering a genome-reduced strain of Mycoplasma pneumoniae, removing the bacteria’s ability to cause disease and repurposing it to attack harmful microbes instead.

‘Living medicines’

Production of biomolecules, such as antibodies, is generally expensive and time consuming. As an alternative, local production of these biomolecules using a living system, such as bacteria, represents an attractive approach to reduce costs and undesired effects associated with systemic administration.

There are already bacterial therapies in different phases of development for a variety of diseases including cancer, metabolic diseases and viral infections. There have also been therapeutic strains that have been reprogrammed to destroy other bacteria. To produce these therapeutic strains, researchers have taken advantage of the mechanisms by which bacteria compete with each other in nature.

Although the field of bacterial therapy is growing, most examples are based on a handful of well-known bacterial genera. These include Escherichia and Lactococcus. In some cases, this is due to the lack of genome editing tools for other bacteria. Fortunately, our ability to edit bacterial genomes is increasing, even in the most genetically intractable genera. This highlights the possibility of adapting other strains as therapeutic vectors. These new vectors in turn might be more suitable for a particular organ and disease than other traditional bacterial vectors.

Why use Mycoplasma pneumoniae as a therapeutic vector?

In this study, published in Molecular Systems Biology, the researchers chose to use the genome-reduced bacterium Mycoplasma pneumoniae as a potential new therapeutic delivery vector. This common species of bacteria lacks a cell wall, making it easier to release therapeutic molecules that fight infection. The lack of a cell wall also helps to assist the bacteria in evading detection from the human immune system. Other advantages of using M. pneumoniae as a therapeutic vector includes its low risk of mutating new abilities, and its inability to transfer any modified genes to other microbes.

Creating a genome-reduced Mycoplasma pneumoniae

The researchers first modified M. pneumoniae so that it would not cause illness. Following that, they modified the bacteria so that it secreted antimicrobial enzymes more efficiently.

The team then made further modifications so that the bacteria produced two different enzymes that are able to dissolve biofilms and attack the cell walls of bacteria embedded within them. Biofilms are colonies of bacterial cells that stick together on a surface. The surfaces of medical implants are ideal growing conditions for biofilms, where they form impenetrable structures that prevent antibiotics or the human immune system from destroying the bacteria embedded within. Biofilm-associated bacteria can be a thousand times more resistant to antibiotics than free-floating bacteria.

Using genome-reduced Mycoplasma pneumoniae

The researchers tested their genome-reduced bacteria on infected catheters in vitro, ex vivo and in vivo. It was found that the modified bacteria was successful at treating infections across all three testing methods. According to the authors, injecting the therapy under the skin of mice infected with antibiotic-resistant bacteria resulted in management of the infection in 82% of the treated animals.

Implications and future directions

The team aim to use their modified bacteria to treat antibiotic-resistant biofilms building up around breathing tubes in patients. This is due to M. pneumoniae being naturally adapted to the lungs.

“Our technology based on synthetic biology and live biotherapeutics, has been designed to meet all safety and efficacy standards for application in the lung, with respiratory diseases being one of the first targets. Our next challenge is to address high-scale production and manufacturing, and we expect to start clinical trials in 2023,” says María Lluch, co-corresponding author of the study.

The authors also noted that the modified bacteria may also have long term applications for other diseases.

“Bacteria are ideal vehicles for ‘living medicine’ because they can carry any given therapeutic protein to treat the source of a disease. One of the great benefits of the technology is that once they reach their destination, bacterial vectors offer continuous and localised production of the therapeutic molecule. Like any vehicle, our bacteria can be modified with different payloads that target different diseases, with potentially more applications in the future,” says Professor Luis Serrano, Director of the CRG and co-author of the study.

Image credit: kjpargeter – Freepik

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Bacteria / Genome Editing / Treatment