The high specificity of bacteriophages for target bacteria is an advantage over antibiotics (phages do not affect beneficial bacteria in the human body), but it also creates problems. Firstly, phages specific to a particular pathogen strain must first be found, which takes time and effort. Secondly, treating a given infection often requires using mixtures of several or many phages to precisely target the target. Currently, phages for phage therapy must be isolated from the natural environment and tested for specificity, and their genome must be sequenced to ensure their safety.

Researchers at the Institute for Food, Nutrition and Health (IFNH) in Zurich, Switzerland, have genetically reprogrammed* phages so that they recognize and attack a wider range of bacterial strains than their wild ancestors.

At the base of their tail, on the basal lamina, bacteriophages possess a specialized protein that recognizes specific receptors on the cell wall of the target bacterium. Using X-ray crystallography, scientists studied the spatial structure of this receptor-binding protein of a phage specific to one strain of Listeria monocytogenes (a bacterium often responsible for food poisoning). Then, using fragments of receptor-binding proteins from other phages, they modeled new functional molecules and, through genetic modification, created synthetic phages that recognized and destroyed a wide range of different strains of L. monocytogenes . The genomes of these phages were identical except for the receptor-binding protein gene.

A cocktail of such phage variants could be used to treat patients—it can kill a large number of different Listeria strains. Synthetic phages are much easier to create such a cocktail than natural ones, as they can be relatively easily adapted to a specific pathogen.

The researchers note that their synthetic phages can be used as probes to search for specific molecular structures and identify pathogenic strains in mixed bacterial populations. They also plan to create synthetic phages capable of destroying other pathogens, particularly those that frequently exhibit antibiotic resistance ( Staphylococcus aureus, Klebsiella pneumoniae , and Enterococcus species ).

Genetically modified phages have only been used once in clinical practice, in a 15-year-old patient with cystic fibrosis who had suffered from a severe mycobacterial infection after a lung transplant. The treatment was successful, but the technology requires further testing.

Another way to adapt phage specificity to clinical needs was recently proposed by researchers from the Massachusetts Institute of Technology. They introduced mutations into the protein that makes up the filaments at the end of the phage tail, creating a huge library of different virus variants, each of which could potentially recognize receptors on the surface of various E. coli strains.

* Dunne M., Rupf B, Tala M et al. Reprogramming Bacteriophage Host Range through Structure-Guided Design of Chimeric Receptor Binding Proteins // Cell Reports, 2019, 29(5): 1336-1350.E4. https://doi.org/10.1016/j.celrep.2019.09.062