Phages: the armageddon of infections?

There is no doubt of the urgent need for developing new antibacterials. The list of bacteria resistant to virtually all drugs is increasing nearly every month and in the XXI century patients are dying in our hospitals due to the lack of treatments for infections. No surprisingly, WHO announced in 2009 that “Antibiotic resistance is one of the three greatest threats to human health”.  Since the drug discovery pipeline is nearly dry, alternative antimicrobial approaches have been proposed, including the use of  antimicrobial peptides, the manipulation of the host-pathogen interphase (followed in my lab with very promising results), and the use of bacteriophages. 

The discovery of bacteriophages, obligate predators of bacteria, is attributed to Twort and d’Herelle in the early 20th century. The therapeutic potential of phages was recognized soon thereafter and applied for several decades before the discovery and widespread adoption of antibiotic. However, there has been a renewed interest into bacteriophage therapy due to the increasing incidence of antibiotic resistance.

D’Hérelle was the first one to use phages to treat dysentery with great success. However, the introduction of penicilin and other antibiotics stopped completely the use of bacteriophages Even the American Medical Association (AMA) recommended not to use phages to treat infections. Nevertheless, in 1923, D’Hérelle helped to create the Eliava Institute in Tbilisi (Georgia) to study bacteriophages and their potential clinical aplications. It should be aknowledged that most of research in bacteriopahge therapy has been carried out in Eastern Europe and the Soviet Union. In fact,  phages were used throughout the 40s in the Soviet Union to treat infections.

Western skepticism of phage therapy is mostly due to the fact that many of the reports describing phage therapy from these countries are not accessible in English and those that are accessible often lacked appropriate controls. However, there are recent published reports demonstrating the efficacy of phages to treat infections in animal models as well as complicated infections in humans, as reported by Polish scientists from the Ludwik Hirszfeld Institute of Immunology and Experimental Therapy. 

Each bacteriophage has a limited spectrum of infectivity against its bacterial targets. Thus, the development and adoption of clinical assays to rapidly identify causative bacterial pathogens and their susceptibility to phages are necessary. Traditionally, a cocktail approach has been used to address the limited host range of any single phage. Modern biotechnology and automation techniques should help to expand phage host range to reduce the number of bacteriophage necessary in a given cocktail. In addition, multi-species enrichment protocols can enable the selection of natural phages with broader infective spectra. I should mention that to isolate bacteriophages from, for example, sewage water, is a very simple method. My students in the context of the General Lab Course of Microbiology have isolated phages against Pseduomonas aeruginosa, Klebsiella pneumoniae, and even Yersinia pestis (though a totally avirulent isolate) just in 4 days and without any previous training.

Bacteria can evolve resistance to phages through a variety of different mechanisms, including blocking phage adsorption, inhibiting the injection of phage genomes, restriction-modification systems, and abortive infection systems. In in vitro monoculture studies, phage resistance can evolve on the order of hours to days. One question that deserves more study is whether the evolution of phage resistance in vitro is relevant to in vivo conditions where bacteria may be replicating more slowly and challenged with a greater set of environmental conditions. We should also take into account that in vivo selected mutants could be eliminated more easily by the innate immune system than the wild-type infecting strain. Supporting this, bacterial resistant mutants selected in vitro display growth problems and their surface is severly compromised.

In conclusion, I do believe that there is enough evidence supporting the use of bacteriophages to treat infections. At the very least, the evidence is solid enough to encourage public and private investments in this area of research. Important challenges ahead are the evolution of phage-resistant bacteria, phage manufacturing, systemic side effects, and phage delivery. Nonetheless, these are the same challenges face by any new drug. The time is ripe to give some credit to these old bacterial enemies!!!