Phage Response? Using the Killers' Weapons

Last week Ansis Helmanis, a Principal at RegLink News asked why bacteriophages are not commercially available for antibiotics use in this country. Bacteriaphages have a century’s worth of research as well as use in medical settings, though largely in Soviet and Eastern Block nations, he explained.   The article generated a quick response, from Markus Matuschka de Greiffenclau, CEO of Lysando AG, Triesenberg, Liechtenstein, below:     Phages are natural agents that combat bacteria going back billions of years. Nonetheless, as antibiotics, phages show inherent disadvantages.    First, phages do not intend to eradicate the target bacterial strains entirely but rather evolve into a balance between “prey” and “hunter”. Therefore, we may assume the obvious fact, if phages were utilized for widely defined applications, as we do today with antibiotics, we will see resistance rising quickly, and consequently, and we will run out of ammunition soon.   Even manipulated or “synthetically upgraded” phages, which include the DNA for Endolysins, AMP’s or even Artilysin®s in its genome  – in a mass application – have inherent disadvantages.   Additionally, phages are always limited to a bacterial genus, species or a limited number of strains within a species. As a result, phage therapies will expire quickly because the targeted strains develop a resistance, or possibly non-addressable pathogenic strains will take over.   Also, phages may pick-up DNA, and that, in combination with their ability to temporarily integrate themselves into the genome of the target bacteria, may cause severe impact. Diseases like cholera or enterohemorrhagic gastroenteritis (EHEC, etc.) are caused by genetic elements transferred between pathogenic bacteria by phages.   Further, it is hard to avoid that such viruses will enter the environment, which in a mass application, similar to antibiotics, is going to happen in large quantities. One may consider ways to avoid such scenarios by pre-selecting or manipulating the phages, but the chances of controlling a biological system are close to zero thanks to endless challenges from billions of years of evolution.   For individual treatments with a profound analysis of the pathogen strains, a well monitored treatment phage therapy may present a good option, but that does not solve the increasing issues we face with resistance towards antibiotics.   However, phages may provide us with a solution; we just have to break it down to the mechanism of interest. Once phages have entered the bacteria they manipulate them to produce further phages, and those leave the bacterial cell at the end of its replication cycle.   In order to do so, phages program the hijacked cells to produce holins and endolysins which lyse the cell from the inside to release the new phage generation. This mechanism can be transferred and used to lyse Gram positive bacterial species as well from the outside. Meanwhile new technologies allow to overcome this limitation, caused by the protection of Gram negative bacteria by their outer cell membrane. If one wants to eliminate Gram positive as well as Gram negative bacteria, it requires a modification of endolysins.   We should not rule out Phages, but we should not use them as bacteria killers. Rather we should consider them as donors of mighty weapons one can use against the growing threats of antibiotic resistant bacteria. We should practice intelligent and advanced protein engineering of lytic proteins in order to achieve a more sustainable, less risk afflicted solution, leaving the bacteria hunting viruses behind.   Markus Matuschka de Greiffenclau, CEO of Lysando AG, Triesenberg, Liechtenstein