oa Editorial [Hot Topic:The ‘Nuts and Bolts’ of Phage Therapy (Guest Editor: Stephen T. Abedon)]

Bacteriophages (phages) are the viruses of bacteria and phage therapy is the application of phages to control or eliminate bacteria and their infections. Phage therapy holds great promise as a means of augmenting the use of chemical antibiotics to control bacteria, including antibiotic-resistant bacteria or under circumstances where antibiotic treatment is less safe or otherwise undesirable. Applications include treatment of bacterial infections of humans, animals, plants, and even fungi (e.g., mushrooms); removal of pathogenic or spoilage bacteria from foods; general disinfection; and disruption of biofilms. Biofilms otherwise can interfere with industrial processes and/or serve as reservoirs of infection, such as within catheters or dialysis machines. The major strengths of phages as antibacterials is their ease of isolation and relative safety while their major disadvantage (though also an advantage) is their narrow spectrum of activity, i.e. host range. The development of an effective phage therapy protocol is a multi-step process. Difficulties at any of these steps can hinder what otherwise can be strengths of using phages as therapeutic agents. These development steps include phage isolation against a specific bacterial strain; testing for activity against that strain as well as against related bacteria; screening for undesirable traits such as the potential to enhance bacterial virulence; growth to high densities; purification away from especially toxins present as residues within bacterial lysates; stabilization for storage; and delivery of viable phages to target bacteria. Ideally, once delivered, phages will survive, not overly stimulate animal immune systems, both adsorb and kill target bacteria, and, in most cases, increase in density and/or spread spatially to reach otherwise minimally accessible bacterial targets. Phages also can be modified using genetic engineering techniques to increase useful characteristics or to decrease potentially detrimental properties. A major concern in the development of phage therapies is regulatory, especially in ways phages differ from standard therapeutic agents. In particular, an ideal environment for phage therapy efficacy appears to be one in which phages may be matched (in terms of host range) to specific bacterial pathogens, evolved toward greater breadth in host range, and/or used as a mixture of multiple phages (a cocktail). Cocktails collectively possess sufficient host-range breadth to treat either a high diversity of pathogens of a specific type or multiple pathogens that can be present as a mixed infection. Phages also are complex chemical entities that are difficult to prevent from evolving. Together these characteristics make phages, at best, simply different from standard chemotherapeutics. At worst, held to the same standards as chemical drugs, phages potentially may be more expensive to move through the regulatory process, which is quite the contrast to a key benefit of phage therapy in places where it already has been approved for human use, such as in the Republic of Georgia: A relatively low cost. Overall, I am guardedly optimistic that phages may come to be increasingly employed as biocontrol agents in a variety of contexts, ranging from agricultural to medical. This special topic issue of Current Pharmaceutical Biotechnology explores the potential of phage therapy within a variety of contexts, taking an especially ‘Nuts and Bolts’ approach i.e., a practical, working guide towards considering what strategies should be most efficacious given real-world application.