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Phages - how do they work?

Bacteriophages, short form: phages (Greek: phagein = eat/swallow) are viruses that exclusively attack bacteria and lyse them (“bacteria eaters”). Phages cannot reproduce alone by themselves, they require the bacterial cell as a host to reproduce within the host. A phage is much smaller than a bacterial cell and consists of its hereditary material (nucleic acid, mostly DNA) that is embedded in a protein envelope. This envelope is the “head” of the phage and has a crystalline shape that is only visible in an electron microscope. Additionally, a phage has a protein “tail” with a morphologically delicate fine structure at the end, for adsorption to the bacterial cell surface, the receptor. This receptor structure is so specific that a phage can only attack bacteria having a cell surface that exactly “matches”. After adsorption to the bacterial surface, the phage injects its nucleic acid into the bacterium that will now be forced to produce a new phage generation by using the bacterial enzyme equipment. One single bacterial cell may produce an enormous number of new phages. It is not only that the pressure forces the bacterium to burst, the phage progeny release is a complicated enzyme-driven process. The phage progeny will immediately kill other bacteria with a surface matching with the phage. This effect is easily visible as lysis holes called plaques on densely grown bacterial layers on agar plates. Hence, the phage activity of intact phage particles can be visualized with the naked eye: a phage plaque has been formed originally by one single phage comparable to a bacterial colony that originates from one cell. Whereas a single phage particle can only be made visible by electron microscopy.

As the number of phages of a new phage generation is usually very high, the phages will quickly and completely attack bacteria in their proximity. This will happen as long as bacteria are available and receptors properly match. This means, also for phage application: phages must have a suitable bacterial host to replicate and to keep “alive”. Among the large numbers of bacterial cells in a certain habitat (this may include also an infection locus like e.g., a wound) a statistical number of bacterial mutations can lead to phage-resistant bacteria (mutation frequency). But, these developing mutants will often remain a minority, the phages will “co-evolve”, they themselves will develop mutations that target the resistant bacteria. As a consequence, the adapted phages will to a certain degree be able to attack the bacteria. This phenomenon called “population dynamics” demonstrates in a simple manner what evolution of phages and their bacterial hosts in a habitat means. In natural environments, such a competition or, often called arms race between bacteria and phages is of particular scientific interest.

But, if phage therapy is envisaged to fight against a dense bacterial patient infection or colonization, attention is drawn to the specific causative bacteria and suitable phages. The “habitat” would not be garden soil or a water pit but a wound of the human body, an abscess, a chronic inflammation, a bacterial biofilm within the airways, an infected burn wound, the bloodstream etc. In such cases, bacterial numbers are often an extreme challenge for the human immune system that in worst case collapses: antibiotics are the last possibility to fight the bacteria. There are many different kinds of antibiotics, they can be allocated to some well-defined chemical substance classes. Antibiotics are more or less specific against bacteria, but never specific for a certain bacterial species and even less against certain strains of a certain species. This is in contrast to phages that attack almost always only one bacterial species and more typically, only few strains of a species. This high specificity is typical for phages because of their biology: a phage-host system is like a key-lock function the reason of which is the global bacterial control and constant bacterial mass turnover by phages as the main superior regulators.

Therefore, phages are a completely different though biologically logic alternative to antibiotics: once a potent lytic and well-characterized phage is found that attacks a pathogenic bacterium, the bacterium can be killed fast, specifically and without known side effects. The phage will leave other bacteria intact like the gut flora or other microbiota (of a patient). After having lysed all target bacteria, the phage will decay and disappear, its components will be metabolized by the human body: when the bacterial number has decreased dramatically, the phage will be target of the reticulo-endothelian system: the therapeutic phage effect is “self-limiting”. Compared to all known medicines or remedies, only phages bear this self-regulating feature.     

As phages are the most abundant free-living entities on earth (probably the tenfold number compared to bacteria), the human immune system knows phages from evolutionary history: we have a constant intake of phages via water, food and contact with natural materials, our gut flora contains enormous amounts of phages, like a complex ecosystem in balance. This and the rather simple composition is probably the reason why phages are not known to cause allergic effects and why, according to several scientific investigations in preclinical and clinical settings the immune response to phages does not get out of control.

Important:
Phages are highly specific and for application, they can hardly be compared with the mode of action of antibiotics. Phages are the natural predators and regulators of the bacterial mass in the biosphere. Their host specificity requires another practical concept for use. Furthermore, phages are individuals regarding their biological properties which means that each phage entity must undergo deep characterization before being recommended for any application.