An the 1031-1032 phages present around the

An era of antibiotic resistance has started since 2015 both the US Centers for Disease Control (CDC) and the World Health Organization (WHO) declared the rising of antimicrobial resistant bacteria strains as a threat to global health. To give an idea of the problem it should be known that 700,000 people die each year globally from antimicrobial resistance bacteria strains and another 2 million become ill in the US alone.1 This problem is partially due to the rapid rate of antibiotic resistance evolution in bacteria, making it less commercial interesting to develop new antibiotic compounds. From 2010-2016 only six antibiotics were approved by the FDA (Food and Drug Administration) compared to the 26 approved in the period from 1983-1987.1 So, new antibiotics are not the solution for the evolving resistance, but what is?About the answer to that question researchers over the world are not on the same line. One of the possibilities is the field of bacteriophages. In the contrast of 6 new antibiotics in the last six years phages (short for bacteriophages) can be selected out of the 1031-1032 phages present around the world. In their native environment, they are responsible for the death of approximately 20% – 40% of all marine surface bacteria.1 In the early days of the discovery of bacteriophages, over a century ago, little was known about viruses. Only after the development of sequencing techniques, the information about the mechanism of action of the bacteriophages became clear.In general, phages can be divided into two main categories: temperate and lytic phages. Temperate phages incorporate their genomic material into the genome of the host cell and reproduce vertically from the mother to daughter cell. However, lytic phages hijack the replication machinery of the host cells, form the produced virus particles the phages spontaneously assemble and lyse the host cells. Even within those categories, phages are incredibly diverse, thereby are phages as are viruses ultimately depended on host cells for reproduction. Classical antibiotics act on prokaryotic specific processes to block the reproduction and in this way fight infections. Since most of those processes are conserved over a wide range of bacteria strains, antibiotics are relatively non-specific. On the contrary, phages are highly specific; a phage uses receptors on the bacterial cell wall to infect cells. In most cases, phages are infectious to a few strains only, referred to as lytic phage host range. As with any other medicine used in humans, the patient safety is extremely important, because of the lack of interest little research has gone into the safety of phages. Therefore, most of the Western government authorities are reluctant to clear phages for use in the clinic. However, promising results about the safety of phage therapy are present in the literature. At least a few clinical one trials showed phages were safe to use.2,3,4 It should be noted that in each of those trials the phage (cocktail) was not administrated into the bloodstream. Instead, it was sprayed directly on the skin. This method of administration can fight infection present in open wounds like chronic otitis, venous leg ulcer and burn damage, in each of those three cases phages (against Pseudomonas aeruginosa) passed the clinical one trials. According to Alexander Sulakvelidze et al. even intravenous administration of phage cocktails did not cause side effects. Thereby, in eastern Europe phages have been administrated to humans (i) orally, (ii) rectally, (iii) locally, (iv) and intravenously. Due to the bad documentation those treatments are mostly not suitable to claim safety but at least indicate no severe reaction from the body against phages.Besides all those positive comments it could be argued that using phages is dangerous. Temperate phages could carry virulent factors that are incorporated as prophages into the genome of the host cell, giving this cell advantages to spreading more quickly. Next to that, there are phages known with genes encoding toxins that are subsequently released in the lytic cycle. However, with the widely available technique for (deep) sequencing, it is possible to select against those phages. Thereby, even with the well-documented risks of antibiotics, unwanted side-effects have been reported. Shortly, the safety of phages is still argued, better clinical and preclinical experiments have to document the risks more thoroughly.  In contrast to the safety, some features of bacteriophages show advantages above antibiotics, without any discussion. Firstly, as mentioned before phages are very common on earth, so in contrast to antibiotics, the discovery of new phages is relatively cheap. Secondly, the auto-dosing of phages shows to be promising. Since phage reproduction is depended on the host bacterial cell, the reproduction is somewhat in correlation to the number of host cells. Thereby, single-dose treatment with phages shows promising effects, because the phage will reproduce until no host cells are available anymore. Thirdly, bacteriophages can penetrate biofilms, where antibiotics lack this ability. Some bacteria tend to form biofilms, in those biofilms bacterial cells are protected by extracellular polymeric substances (EPS). Antibiotics are ineffective against biofilms in normal doses, only high concentrations, mostly out of the safety range, are effective against those structures. However, bacteriophages are equipped with, for example EPS depolymerase, enzymes on their exterior capsid that degrade the EPS and therefore can penetrate the biofilm. Lastly, since phage and antibiotics have unrelated mechanisms of action, it is highly unlikely that there is or will ever be cross-resistance. That together with the diverse nature of the phages and the abundant presence of phages gives us a great pool to screen for phages suitable for therapy. Apart from the just mentioned advantages, bacteriophages are much more specific than antibiotics. This feature is disused in favor of phages as well as in disfavor. As shortly described before antibiotics act on prokaryotic processes common in many bacterial strains. In contrast, phages depend on strain-specific receptors on the bacterial cell wall for their ability to infect cells. Nowadays, the first step in the treatment of infections is a broad-spectrum antibiotic, so that treatment can start without identification of the bacterial strain. In theory, this would be impossible with phage, since there are no such things as broad-spectrum phages. However, in practice it has been proven to be efficient to treat people with cocktails containing various phages. After identification of the bacterial strain then a second dose of the specific phage can be given if needed. Moreover, the narrow lytic range of phages provides phage therapy with even more advantages above antibiotic treatment. Antibiotics may be specific for prokaryotes, broad-spectrum antibiotics will fight gut microbiome too. That has already been associated with risks to develop diarrhea and even asthma, obesity and diabetes. Just like the safety of phage therapy, these kinds of side-effects have been poorly studied for phages. However, since the very narrow lytic host range, it is unlikely that phage therapy will cause severe perturbation of the gut microbiome. Lastly the narrow host range in combination with the fact that phages are composed predominantly of nucleic acids and proteins, it gives them a much lower environmental impact and theoretically less inherent toxicity. It could be argued that phages and especially the crude phage lysate and bacterial components (possible endotoxins) upon lysis can be toxic to the human body. However, researchers suspect these side-effects will only take place when phages are administered in high doses. This speculation is based on the fact that phages are used as therapy already in Eastern Europe. Thereby, Andrzej Górski et al. found evidence for the presence of endogenous bacteriophages, and their initial date even suggests that those endogenous phages help the body fight invaders. These findings suggest that our body can tolerate certain amounts of phages. Since the discovery of penicillin almost a century ago the entire western world has given their faith into antibiotics. Step by step people are getting aware will no longer live in the antibiotic era, but this era has transformed into the antibiotic resistance era. In the era of antibiotics, we have put our faith in the synthetic production and development of drugs not only for antibiotics. Even now we are facing danger for the global health we neglect to learn from nature and its way to fight bacteria. That is partly the result of the industry that has developed the drugs the previous centuries; this industry is a big part profit orientated. Since bacteriophages are a natural product, it would be difficult to patent phage therapy, hence failing to make big profits from the treatment.?Before rounding off this discussion, a short sneak peek into the possibilities of phages has to be given. The rest of this essay is about natural occurring phages, however bioengineered phages and lytic proteins will be the future of antimicrobial therapies. The recent innovations in gene editing tools, like CRISPR/Cas, makes it possible to bioengineer phages in such a way that they, for instance, can deliver a CRISPR/Cas programmed to disrupt antibiotic resistance genes. Furthermore, the lytic cycle of phages is functionally depended on two classes of enzymes, holins, and lysins. The most promising of those two are lysins, peptidoglycan cell wall hydrolases, they break down the cell wall, which causes the lysis of the bacteria. Several different lysins have been identified and displayed activity in vitro and ex vivo. Engineered recombinant phage lytic proteins would be easier to administer, mass produce and get approval by the FDA (since enzymes as pharmaceuticals are less unique). Lastly, the target sites of lysins on the peptidoglycan cell wall are essential for bacterial viability, so it is considered unlikely bacteria will ever evolve resistance to lysins.In conclusion, bacteriophages are viruses for bacteria that display a narrow lytic host range. This narrow lytic host range makes the environmental impact of phages less than that of antibiotics and results in less perturbation of the gut microbiome. Unfortunately, the safety of phage therapy is not yet studied well enough to implement it as standard therapy. However, in the recent years more has become known about viruses in general and phages specifically. With this knowledge and availability of sequencing technique phages can be selected for their lytic character and against genes encoding toxins. Thereby, phages are used as therapy in Eastern Europe for almost a century, for this therapy cocktails composed of different phages, of the lytic class, are used to treat patients. These treatments have proven to be effective against a range of bacterial strains, biofilms, and even multi-resistant strains. Moreover, a few clinical one trials for different phages are performed and did not discover any side-effects.In retrospect, the Western world has ignored nature’s response towards bacteria long enough. Also, physicians in the Western medical world have neglected for almost a century to look at colleagues in Eastern Europe. This carelessness resulted in the raising antibiotics resistance of bacteria we are facing at the moment. Now the times has come we should start with implementing phages as last resort treatment, for otherwise untreatable infections. That has to be realized by screening phages for their suitability as therapy. Thereby, bioengineered phages and lytic phage enzymes have to get the full attention of the industry to develop new antimicrobial therapies. The worst enemy of my enemy is my best friend.