A research group of the Institute of Integrative Systems Biology (I2SysBio), a joint center of the Spanish National Research Council (CSIC) and the University of Valencia (UV), develops a molecule based on bacteriophages or phages to cause bacterial death by depolarization of the cytoplasm, which causes bacterial cells not to maintain the electrical charge to carry out their vital functions.
Infections caused by antibiotic-resistant bacteria will overtake cancer as the leading cause of death in the world by 2050, according to the World Health Organization (WHO). Faced with this threat, a research group at the Institute of Integrative Systems Biology (I2SysBio), located in the scientific-academic area of the Science Park of the University of Valencia (PCUV), is developing a molecule based on bacteriophages or phages, viruses that kill bacteria, to cause their death by depolarization of the cytoplasm, which causes bacterial cells not to maintain the electrical charge to carry out their vital functions and die irreversibly.
Antimicrobial resistance (AMR) causes more than 35,000 deaths in Spain, according to the Spanish Society of Infectious Diseases and Clinical Microbiology. It also causes four million serious infections a year. According to the WHO, by 2050 this major threat to public health, which already causes 700,000 deaths a year, could overtake cancer as the leading cause of death, causing 10 million deaths a year.
Antimicrobial resistance (AMR) causes more than 35,000 deaths in Spain, according to the Spanish Society of Infectious Diseases and Clinical Microbiology.
One of the most promising alternative therapies to conventional antibiotics are bacteriophages or phages. They are viruses that infect and parasitize bacteria, and are the most abundant biological entities on the planet. Each phage is specific to a particular bacterial genus or species, which allows it to be targeted against a specific bacterium. They act like other viruses: they bind to a receptor on the bacterial surface and inject their genetic material into the bacterium, 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 that looks like a phage, but is not. Although these molecules were known, it had never been possible to evolve them, which is necessary to kill bacteria of interest. "These are headless phages, capable of piercing the bacterial membrane, but without introducing their DNA," explains Jaramillo.
Thus, these molecules would induce the death of the bacteria by depolarization of the cytoplasm. "By piercing the membrane, a charge difference is produced where the ions escape, causing the death of the bacterium," 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 grant of nearly half a million euros from the research program of the 'La Caixa' Foundation.
"Bacteria have a defense system that can also make them resistant to phages," argues Alfonso Jaramillo, CSIC researcher at I2SysBio
Phages that are not phages
The i2SysBio research team aims to use evolution to create antimicrobial molecules based on the proteins produced by phages to insert their DNA into bacteria. To this end, they will develop a technology capable of accelerating the evolution of phages a million times, making it possible to obtain headless (capsid) phages. In addition, it will make it possible to anticipate mutations that could make bacteria resistant and thus adapt antimicrobial molecules to these mutations.
Thus, the antibacterials that will be developed thanks to this project are mere clusters of proteins, not viruses. They cannot replicate, neither in the bacteria nor in our own organism, and will be harmless to beneficial bacteria, which will solve one of the undesired effects of current antibiotics.
According to Jaramillo, this strategy maintains the advantages of the phage therapy applied today against AMR, but makes it possible to obtain antimicrobials that avoid possible resistance of the bacteria to the phage. Moreover, since these molecules, unlike phages, do not evolve and are not genetically modified organisms, their sanitary authorization would be simpler. It would also be a faster and cheaper method, since the molecules would be obtained by fermentation in bioreactors.
The project, which has a duration of 3 years starting in January 2023, aims to demonstrate that this technology is useful and viable for the production of antimicrobial agents.
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