The World Health Organization (WHO) considers multi-resistant germs to be among the biggest threats to health. In the European Union alone, 33,000 people die each year as a result of bacterial infections that cannot be treated with antibiotics. So there is an urgent need for alternative treatments or medicines.
Phages, the natural enemies of bacteria, are one promising solution. There are millions of different types of these viruses on Earth, each specialized in a particular bacteria. In nature, viruses use bacteria to reproduce; They insert their DNA into bacteria, where viruses multiply rapidly. Eventually they kill the cell and move on to infect new cells. The bacteria act as a specific antibiotic by attacking and destroying a specific type of bacteria.
Viruses for health
“The phages offer tremendous potential for highly effective personalized treatment of infectious bacterial diseases,” notes Jill Westmeyer, Professor of Neurobiological Engineering at the Technical University of Munich (TUM) Director of the Institute of Synthetic Biomedicine at Helmholtz Munich. “However, in the past, it has not been possible to produce phages in a targeted, reproducible, safe and effective manner – even though these are precisely the critical criteria for the successful production of pharmaceuticals.”
Now the research team has developed a new controlled production method for creating phages for therapeutic use. The basis of this technology was created by A group of students at TUM and Ludwig Maximilian University of Munich (LMU), who was awarded in the 2018 International Genetically Engineered Machines (iGEM) competition. This combination then led to the start-up Invitris, which is currently developing a platform technology for phage-based drugs.
The cornerstone of the new technology, which is already in the patent application process and is now being used in new research at TUM, is a special nutrient solution in which bacteria form and multiply. Nutrient solution consists of extract of Escherichia coli and does not contain viable cells; This is a fundamental difference from previous phage production methods, which traditionally used cell cultures with strains of potentially infectious bacteria.
At TUM Laboratories, the Munich team has now been able to demonstrate the targeted production of phages in a cell-free nutrient solution: the only component required is the genome – normal DNA – of the desired viruses. The genome contains a complete blueprint for phage formation. When DNA is injected into a nutrient solution containing the molecular components and enzymes of E. coli bacteria, the proteins assemble according to a scheme: thousands of identical copies are created in just a few seconds. “This production method is not only fast and efficient, but also very clean — the process eliminates contamination with bacterial toxins or other phages, which are a potential complication in cell cultures,” Westmeyer says.
But is the new cell-free nutrient solution really suitable for producing phages that can be used in individual treatments? The researchers put the idea to the test with the Bundeswehr Hospital in Berlin: Using a bacterial sample from a patient who had an antibiotic-resistant skin infection, the Munich team screened for the new promising bacteria and isolated their DNA. The phage was then produced in a cell-free nutrient solution and finally used to successfully combat multiple resistant bacteria.
Genetic archive for emergencies
“Our studies demonstrate the feasibility of a cell-free method for producing effective phages for personalized drugs that can also be used to treat multi-resistant bacterial infections,” says Westmeyer. In the future, he adds, the methodology could ideally be used with a genetic archive that stores the DNA of related phages. When necessary, this archive can be used to rapidly produce entire phages in a nutrient solution, test their efficacy and then apply phages in appropriate combinations, says Westmeyer, adding that although this work is still in the basic research stage, the method nonetheless has potential to make clinical trials.
chemical cell biology
Cell-free production of personalized therapeutic phages that target multidrug-resistant bacteria
The date the article was published
11 July 2022
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