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 for Integrative Systems Biology (i2SysBio), a joint center of the Higher Council for Scientific Research (CSIC) and the University of Valencia (UV), in Spain, is developing a molecule based on bacteriophages or phages, viruses that kill bacteria, to cause their death by depolarization of the cytoplasm, which means that the cells of the bacteria do not maintain the electrical charge to carry out their vital functions and die irreversibly.
Microbial resistance to drugs already causes more than 35,000 deaths in Spain, according to the Spanish Society of Infectious Diseases and Clinical Microbiology. In addition, they cause four million serious infections a year. In other nations, the figures are equally worrying. According to the WHO, in 2050 this great threat to public health, which already causes 700,000 deaths per year, could surpass cancer as the leading cause of death, causing 10 million deaths per year.
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 certain genus or bacterial species, which allows it to be directed against a specific bacterium. Phages act like other viruses: they bind to a receptor on the surface of the bacterial cell and inject their genetic material into the cell, replicate and destroy it.
However, “bacteria have a defense system that can also make them resistant to phages,” argues Alfonso Jaramillo, a CSIC researcher at I2SysBio. His De Novo Synthetic Biology lab has just begun a project to develop a molecule mimicking ones that already exist in nature that looks like a phage, but isn’t. Although these molecules were known, it had never been possible to improve them in the ideal way, which is necessary to kill the bacteria of interest. “These are headless phages, capable of piercing the bacterial membrane, but without introducing its DNA,” explains Jaramillo.
Thus, these molecules would induce the death of the bacterium by depolarization of the cytoplasm. “By piercing the membrane, a difference in charge is produced where 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.
Artist’s impression of an artificial pseudovirus about to attack a bacterium. (Illustration: Amazings/NCYT)
phages that are not
The I2SysBio research team intends to use evolution to create antimicrobial molecules based on the proteins produced by phages to insert their DNA into bacteria. To do this, they are going to develop a technology capable of accelerating the evolution of phages a million times, making it possible to obtain phages without heads (capsids). 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 groups of proteins, not viruses. They cannot be replicated, neither in the bacteria nor in our own organism, and they will be harmless to the beneficial bacteria, which will solve one of the unwanted effects of current antibiotics.
According to Jaramillo, this strategy maintains the advantages of phage therapy that is applied today against microbial resistance to drugs, but allows antimicrobial agents to be obtained that prevent possible resistance of the bacteria to the phage. In addition, since these are molecules that, unlike phages, do not evolve on their own and are not genetically modified organisms, their health authorization would be easier. 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 from January 2023, has the goal of demonstrating that this technology is useful and viable for the production of antimicrobial agents. (Source: CSIC)