Our trust in modern medicine is currently eroding as we come to realize the global health crisis that is caused by pathogens that are resistant to many, if not all, antibiotics. Soon, we will be exposed to a situation similar to the era before the discovery of Penicillin, where an ordinary injury, a simple cut -if infected- could result in our lives coming to an abrupt end.1 With the emergence of bacteria that are antibiotic resistant [antimicrobial resistance (AMR)], governments of many countries have recognized the criticality of this issue and have started programmes to understand the molecular and evolutionary basis of AMR, in order to avoid the spreading of resistance and to develop novel treatments against multi-drug resistant pathogens.
Phage therapy – an opportunity
While it has been continuously practiced in Eastern Europe, phage therapy currently experiences a renaissance in Western medicine as an alternative for the treatment of bacterial infections (Figure 1).2–7,9 In contrast to their pharmaceutical counterparts, phages can provide versatility of being highly specific towards the pathogen, or eliminating bacteria of certain groups. Phage discovery has shown that phages which kill only one specific serotype of a bacterial strain can be isolated while the opposite is also true – phages that kill across species can be isolated as well. Yet bacteriophages are anything but the “perfect predator.” Evolution “designed” phages not to completely eliminate their host, which is the optimal outcome of any medical strategy to treat infections. However, phage-resistant strains have emerged quickly.8
Phage therapy is “personalized” medicine
Phages are highly strain specific and must be matched to the host which is causing the disease. In this context, “personalized” does not refer to the patient but rather to the infectious agent. Hence, phage therapy cannot be a solution as it is currently practiced. At the time of writing, phage therapy has only been approved in cases that would otherwise lead to patient death. In such instances, large phage libraries have to be rapidly screened to find potential “cures,” phages need to be produced in large quantities and purified, removing endotoxins and other cellular debris, to government safety standard levels. This process of screening and production requires time that is not available and cost-intensive. Thus, not only fast production methods have to be developed but also rapid screening techniques.
Past, present, and future
The years following the discovery of penicillin as the arch compound to treat bacterial diseases in 1928, had mankind convinced that we had already won the fight. For a long time the opinion prevailed that no alternative strategies would be required. Scientists would just find the “next penicillin.” Yet antimicrobial resistance mechanisms emerged quickly with the first resistant bacteria reported soon after the use of penicillin.9 Nonetheless, researchers developed novel compounds and it seemed that mankind would just play a red queen game with the bacterial world, where evolution and co-evolution would run its course. Now, we are at a time point with a unique constellation to our disadvantage: the industry is facing the dilemma of not being able to produce a profitable chemical compound, as novel drugs are kept as reserve antibiotics, and will never be sold on a large scale, while the discovery and testing process from compound to approval costs millions of US dollars. Thus many programs in major pharmaceutical companies are being discontinued10 as we seem to reach the end of the arms race, not being able to provide more tools of war against the microbial world.
What is required to develop phage therapy to make it a standard medical strategy? Aside from faster screening methods of natural phages, we should make use of the biotechnological toolkit that is available to us to engineer genes and create new, synthetic phages. From a biochemist's viewpoint, viruses are nothing more than a protein shell containing nucleic acids. One approach could be to develop a minimal phage cassis that can replicate well in a wide range of target bacteria. Hybrid phages with interchangeable tails, adaptable for the target bacteria can be created. Most phages in nature consist of a head that is almost 100% identical within the different phage types, while the tail structures show only a low percentage of homology. For selectivity, this cassis must then be combined with the receptor binding proteins (RBPs), which have to be collected from nature, selected by in vitro evolution in the lab, or designed using in silico methods. The choice of RBPs will then determine the strain killed by synthetic phage, and multivalent phages with multiple RBPs could expand the host range, if the therapeutic phage is intended to be used on a wider range of bacteria.
There are two ways to develop such cassis phages. One way is to reduce the complexity of the genome of known phages, removing “un-necessary” genes. The other way is to go from simple to complex; the use of microviruses, ssDNA, or RNA viruses might be advantageous because of their small size and the fact that they are non-transducing. Whichever way we decide to develop new phage therapy tools, it is clear that both paths stem from the same pool of limited information.
While we try to develop ways to improve treatment strategies, our understanding of how phages infect their hosts, are replicated and how bacteria defend themselves, is far from being fully understood. Developing therapeutic phages requires our understanding of each gene (and protein) function first. Yet, many phage genomes are not even fully sequenced, much less the molecular function of their gene products understood. It is high time that biologists with molecular and biochemical knowledge stand united with microbiologists and clinicians in the never-ending battle against pathogens. Governments have to realize that the fundamental understanding of the processes involved in AMR and phage-bacteria interaction are as important, perhaps even more important, than developing intermediate solutions. Phage therapy should not be the last resort. History has provided enough evidence of its success in the past.
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