Bacteriophages, or viruses that infect bacteria, were on the cusp of becoming medical therapies in the middle of the twentieth century. But before the viruses got a shot in clinics, researchers discovered the wonder drugs that we now know as antibiotics. With those drugs now failing as pathogenic bacteria grow ever more resistance to classic and modern antibiotics, researchers are once again eyeing bacteriophages (or just “phages” to their friends) as attractive tools for combating infectious diseases.

This past July, the National Institute of Allergy and Infectious Diseases hosted a conference on bacteriophage therapy with the stated goal of developing phages as “a means to specifically target antimicrobial resistance while preserving the natural microbiome.” Phage-based treatments can fight infections while helping to preserve the microbiome (our normal bacterial communities) because the viruses are much more specific than the broad-spectrum antibiotics now in use.

Today, those antibiotics indiscriminately kill a large range of microbes they encounter. But at the time researchers first developed and promoted antibiotics, they were unaware of the human microbiome's existence, let alone its importance.

During the conference, participants had wide-ranging perspectives on the practicality of using phages for therapies. Representatives of the biotechnology industry tended to be very enthusiastic, while physicians remained skeptical. But all participants agreed that medicalized phages are ready for a second shot.

The most promising viruses for use in clinics are tailed phages called Caudovirales, which are the most diverse and numerous biological entities that exist. (As viruses, there is debate as to whether or not they are actually alive; hence “biological entities” rather than “organisms.”) These bacteria-loving viruses work just like the viruses that infect human and mammalian cells. Phages inject their genome, in this case a linear stretch of double-stranded DNA, into a cell. Inside, the viral genomes hijack the cell's machinery to translate themselves into hundreds of viral progeny, which end up exploding out of the cell. The only difference between phage and other viruses is that the target cell is a bacterial cell, possibly a human pathogen.

To find such a phage that would bump off human pathogens, researchers used to isolate naturally occurring phages and then screen them to identify what bacterial cells they infect—a laborious task. We can still do it that way, but with 70 years of molecular biology advances under our belt, we can also isolate the phage components responsible for the different phases of the phage life cycle and just use those for therapies.

Among the potentially therapeutic phage components are lysins, the enzymes responsible for injecting phage DNA and releasing the viral progeny. These enzymes can kill Gram-positive bacteria really quickly and have not yet generated resistance. They're also specific at the genus level. Another option is tailocins, which are molecules similar to phage tails. They can also be lethal to bacteria and can be engineered to target a bacterial cell of choice. Or, we can just design full phages tailored to various hosts; synthetic biologists are already looking to identify and mix-and-match the virulence and specificity of extant phages.

In developing such therapies, researchers are likely to target bacterial pathogens that are resistant to conventional antibiotics, like certain strains of Staph or C. difficile. But to date, the only registered clinical trial of phages is the Phagoburn study, which is evaluating the safety and efficacy of two therapeutic phage cocktails to treat either E. coli or P. aeruginosa burn wound infections in patients in Belgium, France, and Switzerland.

A few things need to be squared away before phage therapy becomes mainstream practice. Although phages are harmless to our cells, they do explode bacteria within our tissues, potentially triggering immune responses. So researchers need to work out some safety standards. Phage researchers also need to catalogue and standardize disparate collections of phages as well as work out assay for determining their clinical efficacy—killing bacteria on an agar plate is not going to cut it.

Science, 2015. DOI: 10.1126/science.aad6791 (About DOIs).