The Post-Antibiotic Phage

It is a well-known fact that we are rapidly running out of antibiotics, in both human and veterinary medicine. The time for the “blame game” is over; we need to start seriously looking for alternative methods to control bacterial diseases in a post-antibiotic era. Fortunately, there are a few options open to us, including discovery of novel antimicrobials, improved vaccine development, improved biosecurity and the use of bacteriophages. All of these options have their place, but here I will focus on bacteriophages.

The concept is sound: make use of viruses that specifically target bacteria to treat bacterial infections. The idea is actually not new – bacteriophages were first discovered in 1917, well before the first human use of antibiotics in 1935. With the discovery of antibiotics, most research into bacteriophages as antimicrobial therapy stopped, but as the problem of antibiotic resistance grows, bacteriophages may be ready for a renaissance.

The potential advantages of bacteriophages include the fact that they are very host specific. Phage therapy can therefore be designed to target specific pathogenic bacteria and leave the normal, non-pathogenic microbiota untouched. Another potential advantage is that the phages are self-replicating, so even small doses could provide effective treatment. There are already a large number of known bacteriophages for most pathogenic bacteria. Plus, there is a huge untapped pool of bacteriophages in the environment, giving us an almost limitless supply of novel phages should resistance develop.

Unfortunately, the main advantage of phage therapy is also its main disadvantage – high specificity. In itself this is not a bad thing, but when it comes to large-scale phage therapy, it is a huge problem. We are highly unlikely to find a single phage that will target all strains of a potential pathogen, for example, E. coli. There are two possible solutions. One is to make use of a cocktail of phages, which pushes up the price of treatment. Moreover, such indiscriminate use of bacteriophages will rapidly lead to resistance. The other option is to select the correct phage for the pathogen. Therefore, the successful use of phage therapy will be highly dependent on substantially improved laboratory-based diagnostic services to classify pathotypes or other molecular markers.

The technology to produce bacteriophages on a commercial scale is not problematic. There is a growing number of commercial companies that are starting to produce bacteriophages and the FDA approval of bacteriophages for the control of Listeria species on poultry products highlights the viability of producing and marketing bacteriophages.

Bacteria are not just sitting ducks waiting to be killed by any passing bacteriophage. They also have protective mechanisms. The restriction enzymes that have become everyday tools in the molecular biology lab are actually bacterial defense enzymes, used to attack infecting bacteriophages. Another potential problem with phage therapy is the possibility of the host developing resistance (immunity) to the phages over time – an important aspect to consider in long-lived humans.

Another more sinister problem with phage therapy also needs very serious consideration. With the advent of full genome sequencing, the scientific community are only now starting to understand the complex relationship between bacteria and bacteriophages. There is an ever-increasing volume of work showing that many deadly bacterial toxins are actually phage-encoded. Phages have the ability to move genetic material from one bacterium to the next, which has resulted in the “creation” of deadly bacterial pathogens. The indiscriminate use of bacteriophages to treat bacterial infections could result in the development of a new deadly “superbug”...

Phage therapy has great potential, but it must be approached with care. We don’t want to replace our problem with a potentially more serious one.