Akin to building with Lego blocks, the researchers assembled new receptor binding proteins by fitting together protein components derived from different phages to provide different host specificities. Finally, the researchers genetically modified
Listeria
phages with their designer receptor binding proteins, resulting in phages that recognize and kill new strains of the target bacterium. Although these designer phages attack different new hosts, they all share the same genome, except for the gene encoding their receptor binding proteins.
Phage cocktail as a form of therapy
A mixture of such phage variants could now be used to treat patients. “We could cover a broad range of hosts by administering several synthetically produced phages in a single cocktail,” Kilcher explains. The difference to a wild-type phage cocktail is that the synthetic ones could be developed, produced and adapted in a much more targeted fashion. Cultivating artificial phages in pure culture is neither expensive nor labor-intensive. “We can program them accordingly for almost every specific purpose,” he adds.
Alongside therapeutic applications, the researchers could also use the synthetic phages as diagnostic markers of specific molecular structures, such as for detecting pathogenic strains among a mixed bacterial population.
A long road ahead
There are still many hurdles to overcome before therapies with genetically modified phages enter clinical practice. The present study is merely a proof-of-concept relating to
Listeria
as a model bacterium, which occurs in food and can cause severe infections in people with weak immune systems.
The researchers are now planning to create artificial phages to combat other pathogens that are often difficult to treat with conventional therapy as a result of antibiotic resistance. Examples include
Staphylococcus aureus, Klebsiella pneumoniae,
and
Enterococcus
species. The methods for engineering such phages are yet to be developed. “Every phage and every host organism harbor particular challenges,” emphasizes ETH Professor Martin Loessner, co-author of the study and director of the Laboratory of Food Microbiology at IFNH. However, he thinks it is just a matter of time before a workbench is also developed for such pathogens.
Much hope is invested in phage therapies. Genetically modified phages have already been used therapeutically in one case. A few months ago, American researchers reported in the journal
Nature Medicine
on a case in which a 15-year-old who suffers from cystic fibrosis was administered phages in order to heal a severe infection caused by mycobacteria. The treatment worked. But broad-based clinical trials are still needed before any phage therapies can be approved.