A bacteriophage, also known as a phage, is a naturally-occurring virus with the awesome capability to infect and kill bacteria by injecting their DNA into bacterial cells which replicates until it kills the host. Phages are the most abundant microorganism in the natural world, occurring in seawater, soil, and in humans. Phages are highly host-specific, only infecting and killing an individual species of bacteria. Compared to antibiotics, phages do not indiscriminately kill bacteria, meaning they do not damage the beneficial gut microbiota, leaving it intact. This specificity has led to phages being seen as magic bullets in the fight against antibiotic resistance. However, the high specificity of phages is also a disadvantage, with bacteriophages having to be isolated from their natural environment, tested against the bacterial strain, and having their genomes sequenced to ensure they are safe for use in humans in time-consuming and expensive tests. Now, a study from researchers at ETH Zurich produces synthetic phages with the ability to recognize and attack a broader range of bacterial strains beyond their natural host range. The team states their platform paves the way for the therapeutic use of standardized, synthetic bacteriophages to treat bacterial infections. The opensource study is published in the journal Cell Reports.
Previous studies show phages recognize their target bacteria with unmatched specificity, a property mediated by receptor binding proteins. These receptor binding proteins, which are found on the bottoms of phage tails, recognize specific receptors on the exposed cell walls of a target bacterium. As phages are extremely diverse in structure and genetic composition, each isolate or cocktail component must be sequenced and properly characterized before it can be used safely in a medical application. To circumvent these issues, it may be possible to engineer a limited number of well-characterized phages to bind and infect the strains of interest. However, this approach requires an in-depth molecular understanding of RBP-host interactions, which is often lacking. The current study uses X-ray crystallography to decipher the atomic structure of the first receptor binding protein from a Listeria phage, to re-engineer synthetic phages.
The current study assembles new receptor binding proteins by fitting together protein components derived from different phages to provide different host specificities. Results show the genetically modified Listeria phages with their designer receptor binding proteins yield in phages capable of recognizing and killing new strains of the target bacterium. Data findings show although these artificial phages attack different new hosts, they all share the same genome, except for the gene encoding their receptor binding proteins.
The lab explains a mixture of phage variants could now be used to treat patients, covering a broad range of hosts by administering several synthetically produced phages in a single, quick to make, targetted treatment. They go on to add the synthetic phages could also be used to detect pathogenic strains among mixed bacterial populations.
The team surmises they have successfully reprogrammed a phage bacterial specificity through synthetic receptor binding proteins. For the future, the researchers state they now plan to engineer artificial phages to combat antibiotic-resistant pathogens, such as Staphylococcus aureus, Klebsiella pneumoniae, and Enterococcus species.
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