A study by the Institute of Integrative Systems Biology (I2SysBio), centre of the Higher Council for Scientific Research (CSIC) and the University of Valencia (UV) located in the University of Valencia Science Park (PCUV), reveals how certain viruses called phages that only infect bacteria modify some of their proteins and share fragments of their genetic material to be able to cross the protective layer (capsule) that surrounds many bacteria and prevents them from entering. This finding opens the door to designing more effective phage therapies against infections caused by antibiotic-resistant bacteria.
The research, led by Celia Ferriol-González and Pilar Domingo-Calap, reveals the evolutionary mechanism that allows phages (viruses with therapeutic interest) to infect bacteria resistant to various antibiotics. The results of this study, published in PLOS Biology, open up new ways to develop more effective therapies against these multiresistant bacteria, which are on the increase.
Phages, also called bacteriophages, infect bacteria and destroy them. They are present in all ecosystems and are considered a promising tool for fighting antibiotic-resistant bacteria. This work analyzes how they adapt to attack different species of bacteria of the genus Klebsiella, responsible for serious hospital infections and with a high resistance to antibiotics, so that they are included in the list of priority pathogens of the World Health Organization (WHO).
"The phages infecting Klebsiella are of great interest because of the threat posed by this bacterium in clinical settings. Understanding how they evolve and adapt is fundamental to developing more effective and personalized phage-based therapies for each patient", Celia Ferriol-González, I2SysBio researcher
These bacteria have a kind of external shield that protects them, called capsule, which varies greatly depending on the variant within the same species (strain) and acts as a barrier against phage entry and also limits the effectiveness of antibiotics. Previous studies by the I2SysBio group of Environmental and Biomedical Virology, led by Pilar Domingo-Calap, showed in two investigations that most Klebsiella phages depend on the capsule to attack bacteria, usually infecting one or a few capsular types.
To infect, some phages need to recognize the capsule of the bacteria. So-called specialist phages attack only a particular type of capsule, while generalists can infect strains with different capsules. For their attack, phages use specialized proteins, called receptor binding, which recognize viral receptors on the surface of bacteria. This study shows that these proteins are much more "flexible" in generalist phages, allowing them to evolve rapidly and attack multiple capsular types. In contrast, specialist phages have more rigid proteins, which limit their adaptability.
"The use of phages as therapy is increasingly on the rise, but much remains to be understood. Understanding the mechanisms of phage-bacteria interaction, viral evolution and adaptation, and how these interactions affect the balance and diversity of microbial communities will lead to more effective treatments", Pilar Domingo-Calap, I2SysBio researcher and co-founder of Evolving Therapeutics
The study also shows that phages can recombine parts of their genome, including key proteins, which accelerates their adaptation to the wide variety of capsules presented by bacteria and allows them to infect new strains. "The difficulty of the trial was to follow the evolution of different phages in the same viral community and their adaptation to a complex environment with many bacteria and capsule types," explains Celia Ferriol-González, co-author of the article. This finding opens new avenues for phage-based therapies against resistant infections, a growing public health problem.
"The phages that infect Klebsiella are of great interest because of the threat posed by this bacterium in clinical settings. Understanding how they evolve and adapt is fundamental to developing more effective and personalized phage-based therapies for each patient," says Celia Ferriol-González.
The study confirms that the flexibility of certain proteins and the genetic exchange between phages are mechanisms that could be used in clinical applications. "This study is a step forward in the design of personalized therapies based on phages and opens the door to use directed evolution to optimize proteins of interest and expand the range of action, as we have shown," explains Pilar Domingo-Calap.
The research also underlines that much remains to be discovered about phage-bacteria interaction and its impact in complex environments. "The use of phages as therapy is increasingly on the rise, but much remains to be understood. Understanding the mechanisms of phage-bacteria interaction, viral evolution and adaptation, and how these interactions affect the balance and diversity of microbial communities will lead to more effective treatments. Our group is advancing in this field, from fundamental science to therapeutic application, through our spin-off Evolving Therapeutics," he concludes.
Evolving Therapeutics is a spin-off of the Universitat de València located in the PCUV business area, which is characterized by its pioneering approach to phagotherapy, a natural alternative to combat multi-resistant bacteria. Founded in 2023 by Marisa and Pilar Domingo Calap, the company works under the One Health paradigm, developing innovative and environmentally safe solutions that improve the health of people, animals and plants. Its global leadership in this field positions it as a benchmark for disruptive biotechnology and the transfer of knowledge from academia to market.
Source: Delegación CSIC Comunitat Valenciana