What are bacteriophages and how do they work?

Bacteriophages (Greek: “bacteria eaters”, short: phages) are viruses that are specialized in infecting bacterial cells, multiplying in them and destroying them in the lytic process. When this happens, a complicated process takes place: the phage recognises the bacterial cell by its surface structures (receptors), adsorbs firmly to the cell with its tail fibres, injects its genetic material out from its head (capsid) through its tail into the cell and induces it to gradually produce new phage particles. This process is controlled by enzymes and an interaction of bacterial and phage genes. Enzymes are also involved in the release of the new phage generation (lysis) from the cell, the cell bursts. The receptors of the bacterial cells that can be recognized by phages are biochemically or structurally different. Phage tail fibres and bacterial receptors must fit like keys and locks, so that phages “work” and can kill the suitable bacteria by lysis.

 

 

 

In principle, phages can be found wherever the right bacterium can be found. Due to their role in nature, phages are very stable in the environment and contribute significantly to the regulation of the global bacterial mass. However, they are specific and almost always only infect strains within one bacterial species, rarely crossing species boundaries. Although phages are living forms of existence, the most common in the biosphere, they are not organisms because they have no metabolism. Bacteria and phages are ubiquitous globetrotters that are subject to constant evolution, and they develop together in co-evolution. These processes take place in all conceivable natural habitats, but also in the human or animal microbiome. Only gradually is the role of the complexity of the human microbiome, the totality of microbial life in and on us (intestines, skin, respiratory tract incl. lungs), recognized. This includes all bacteria and phages, which are ideally in balance.

Coliphage, electron micrograph, coloured
Coliphage, electron micrograph, coloured (Leibniz Institute DSMZ (Dr. I. Korf, Dr. J. Wittmann) and HZI, ZEIM, Central Unit for Microscopy (Prof. M. Rohde))

In medicine, antibiotic-resistant bacteria, including multi-resistant and even pan-resistant bacteria, are playing an increasingly important role. The problem is developing into a global crisis, which was already addressed by the WHO in its first survey report in 2014. In early 2017, the WHO published a “Priority Pathogens” list of bacteria that are most frequently involved in multidrug-resistant infections and require the greatest action with regard to supplementary antibacterial therapies. The bacteria concerned belong to the frequent globetrotters mentioned above, such as Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecium, Staphylococcus aureus, etc.. If they are involved as multi-resistant strains as so-called hospital bugs or permanently colonize weakened people, these infections often become life-threatening.

Susceptibility test of two MRSA patient isolates against 10 different phages
Susceptibility test of two MRSA patient isolates against 10 different phages. Photo: Leibniz Institute DSMZ (Dr. I. Korf)

The effect of lytic phages is therefore urgently desired, especially since no significant side effects have been described in phage therapy and some phages penetrate biofilms better than antibiotics. Phages are the only drug that reproduces itself at the site of infection and disintegrates again after lysis of all suitable bacteria. Phages thus have a self-regulating effect. Since several phage types may be suitable for one bacterial pathogen from a set of available phage types, the therapeutic use of such mixtures of different phage types is optimal. This not only suspects their synergistic effect but also reduces the naturally occurring bacterial phage resistance. Phages for therapeutic purposes are carefully selected on the basis of various properties, an important aspect being the lowest possible occurrence of bacterial resistance. From a general point of view, bacterial phage resistance has no negative consequences comparable to antibiotic resistance because it does not spread as an environmental burden, is not transferred by horizontal gene transfer between bacteria and new phages can be found for most bacteria at any time. The specificity of phages represents a major advantage over antibiotics but is also the main reason for the individual character of phage application as a tailor-made therapy in individual cases.