Infections caused by antibiotic-resistant bacteria will overtake cancer as the world’s leading cause of death by 2050, according to the World Health Organization (WHO).
Faced with this threat, a research group from the Institute of Integrative Systems Biology (i2SysBio), a joint center of the Higher Council for Scientific Research (CSIC) and the University of Valencia (UV), is developing a molecule based on bacteriophages or phages, viruses that kill bacteria, to cause their death by depolarization of the cytoplasm. This mechanism ensures that the bacteria cells do not maintain the electrical charge to carry out their vital functions and die irreversibly.
Antimicrobial resistance (AMR) already causes more than 35,000 deaths in Spain, according to the Spanish Society of Infectious Diseases and Clinical Microbiology. In addition, it causes four million serious infections a year.
According to the WHO, in 2050 this major threat to public health, which already causes 700,000 deaths per year, could overtake cancer as the leading cause of death, causing 10 million deaths per year.
One of the most promising alternative therapies to conventional antibiotics is bacteriophages, or phages. They are viruses that infect and parasitize bacteria, and are the most abundant biological entities on the planet.
One of the most promising alternative therapies to conventional antibiotics is bacteriophages or phages.
Each phage is specific for a bacterial genus or species, which allows it to be directed against a specific bacterium. They act like other viruses: they bind to a receptor on the bacterial surface and inject their genetic material into it, replicate and destroy it.
However, “bacteria have a defense system that can also make them resistant to phages”, argues Alfonso Jaramillo, CSIC researcher at I2SysBio. His De Novo Synthetic Biology laboratory has just started a project to develop a molecule that mimics those that already exist in nature and looks like a phage, but is not.
Although these molecules were known, it was never possible to evolve them, which is necessary to kill the bacteria of interest. “They are headless phages, capable of perforating the bacterial membrane, but without introducing their DNA”, explains Jaramillo.
Bacteria have a defense system that can also make them resistant to phages.
Afonso Jaramillo
Thus, these molecules would induce the death of the bacteria by depolarization of the cytoplasm. “By perforating the membrane, a difference in charge is produced through which the ions escape, causing the death of the bacteria”, says the CSIC researcher. “There is no known bacterial resistance against this effect,” he says.
His team intends to develop these molecules by combining genetic engineering with evolution, thanks to a subsidy of almost half a million euros from the research program of the ‘La Caixa’ Foundation.
phages that are not
The I2SysBio research team intends to use evolution to create antimicrobial molecules based on proteins produced by phages to insert their DNA into bacteria.
For this, they are going to develop a technology capable of accelerating the evolution of phages a million times, making it possible to obtain headless phages (capsids). In addition, this will allow anticipating mutations that can make bacteria resistant and thus adapt to antimicrobial molecules.
The antibacterials that will be developed thanks to this project are mere groups of proteins, not viruses. They cannot be replicated, either in bacteria or in our own body, and will be harmless to beneficial bacteria, which would solve one of the unwanted effects of current antibiotics.
Researchers will use evolution to create antimicrobial molecules based on proteins produced by phages
According to Jaramillo, this strategy maintains the advantages of phagotherapy, currently applied against ADRs, and allows obtaining antimicrobials that prevent possible resistance.
Furthermore, since they are molecules that, unlike phages, do not evolve, and are not genetically modified organisms, their health authorization would be easier.
It is also a method that could be faster and cheaper, since the molecules would be obtained by fermentation in bioreactors.
The project, which will last for 3 years starting in January 2023, aims to demonstrate that this technology is useful and viable for the production of antimicrobial agents.
