Bacteriophages: How Bacterial Viruses Could Be Medicines of the Future

Recently, bacteriophages have attracted more and more attention as an alternative to antibiotic treatment. Trends asked an expert to tell about them everything that is known to science today

What are bacteriophages

Bacteriophages are viruses of bacteria. All organisms on Earth have tiny, invisible parasites in an optical microscope – viruses. They are also found in unicellular organisms.

The reproduction cycle of bacterial viruses usually ends with the death of the microbe. However, there are varieties of bacteriophages that do not directly destroy the host cell, but, like viruses of more advanced organisms, leave it depleted but viable.

Bacteria dominate the Earth’s biosphere, accounting for more than 90% of its biomass. Each type of bacteria has many specialized types of viruses. Bacteriophages are the most numerous creatures in the biosphere. They have been studied for over a hundred years.

Who discovered bacteriophages

In the last quarter of the 1890th century, thanks to the germ theory of infectious diseases by Pasteur and Koch, progress in the field of experimental microbiology accelerated. In particular, scientists have learned how to cultivate microorganisms. Researchers regularly observed an unusual effect: a growing culture of bacteria suddenly self-destructed for reasons unknown at the time. The existence of the smallest infectious agent, capable of passing through the finest filters and causing the death of bacteria, was identified in the late XNUMXs.

However, the nature of this agent remained unclear. At the same time, researchers were actively studying viruses. In 1917, the French-Canadian naturalist Felix D’Herelle succeeded in comparing these two lines of experimental findings and substantiating this in a discussion with scientific opponents.

The main problem of early work in the field of bacteriophage biology was the limited experimental methods available at that time. The researchers had to work with an invisible organism, many of whose properties were impossible to interpret. What a bacteriophage looks like was discovered only in the 1940s with the advent of electron microscopy.

How bacteriophages work

The infectious cycle of bacteriophages follows the same main stages as those of other viruses. The bacteriophage must attach itself to the bacterial cell and deliver its genetic material inside it. Further stages in the development of the infection switch the mechanisms of the vital activity of the bacterium to the maintenance of the bacteriophage, the reproduction of its genome, the construction of copies of the viral envelopes, the packaging of the nucleic acid of the virus in them, and, finally, the destruction of the infected cell. Each of these stages has many nuances that have a deep evolutionary and ecological meaning.

The role of bacteriophages in the biosphere is the regulation of the abundance and diversity of unicellular microorganisms. Bacteria and their viral parasites have coexisted for billions of years. And this struggle for survival did not end either with the total destruction of unicellular organisms, or with the acquisition of total resistance to phages and the uncontrolled reproduction of bacteria.

The most common bacteriophages

The dominant species of bacteriophages in nature are the caudate ones. The tail of different lengths and shapes ensures the attachment of the virus to the surface of the host bacterium, the head serves as a repository for the genome. Genomic DNA encodes structural proteins that form the “body” of the bacteriophage and proteins that ensure the multiplication of the phage inside the cell during infection.

We can say that a bacteriophage is a natural high-tech nanoobject. For example, phage tails are a “molecular syringe” that pierces the wall of a bacterium and injects its DNA into the cell as it contracts.

What are bacteriophages capable of?

During the early period of study of bacteriophages, in the 1920s and 1930s, their only reliably understood property was the ability to destroy bacteria, including pathogens. Researchers in the field of medicine immediately became interested in this property. The first attempts to treat dysentery, wound infections, cholera and typhoid with phages were carried out, albeit not according to modern standards, but quite accurately. Success looked quite convincing. Promising were attempts to fight with their help against bacterial diseases of animals and plants.

However, after the start of mass production and the use of phage preparations, euphoria turned into disappointment. At that time, very little was known about what bacteriophages were, how to produce them, purify them, and use their dosage forms.

In the 1940s, the approach of using in medicine low-molecular substances that kill microorganisms, antibiotics, turned out to be more promising. These substances were easier to manufacture, store, and most importantly, they quickly and efficiently destroyed all microbes in the human body.

But bacteriophages turned out to be surprisingly convenient model objects for studying the fundamental laws of rapidly developing molecular biology. Many of the most important discoveries, without which modern science is unthinkable, for example, DNA recombination and the decoding of the “triplets” of the genetic code, were made with the help of bacteriophages. Enzymes isolated from bacteriophages have become classics of genetic engineering.

Deciphering the genomes of organisms also began with small phage genomes. With the development of experimental genomics, scientists have learned more and more about the colossal role of bacteriophages in ecology and the evolution of the biosphere. Studies of metagenomes, the complete genetic material of biological communities, carried out in the early 2000s, shed light on the enormous diversity of bacteriophages in nature. For example, the CRISPR-Cas system was discovered.

Since bacteriophages are easy to culture and these viruses have a symmetrical structure, they turned out to be convenient models for the development of methods for studying the structure of biomolecules. For example, cryoelectron microscopy, now the gold standard in structural biology, began in the 1990s with reconstructions of the inner envelopes (capsids) of bacterial viruses. The capsids of some phages are able to independently assemble into spatial structures. This is a convenient way to obtain biodegradable protein nanoparticles – “capsules” for targeted drug delivery.

What is the potential of the study of bacteriophages

The potential for detailed studies of bacteriophages is still very high, both in fundamental and applied contexts.

There is renewed interest in bacteriophages as therapeutic agents. In recent decades, the use of antibiotics has raised more and more questions. There is a problem of finding additional and alternative means of combating pathogenic bacteria. In contrast to the situation a century ago, enough is known about bacteriophages to reasonably select those that are suitable for therapeutic purposes. Many aspects of the behavior of phages in the human body and their interaction with the immune system have been studied.

To develop and produce an effective drug, it is necessary to accurately select bacteriophages with fully decoded genomes, cultivate them according to modern biotechnological standards on certain bacterial strains in chemically pure media, and carry out a high degree of purification. However, it is still cheaper than the creation of modern complex antibiotics. In addition, the use of bacteriophages and antibiotics for medical purposes do not contradict each other. When used together, synergism is observed – mutual strengthening of the antibacterial effect. This allows, for example, to reduce the doses of antibiotics to values ​​that do not cause pronounced side effects. A number of papers have been published that describe in detail the successful cases of curing infections resistant to antibiotics using bacteriophages.

Why the study of bacteriophages is criticized in the scientific community

Of course, bacteriophages are not omnipotent. There are a number of fundamental limitations to their use. First of all, the very high specificity of the action. On the one hand, this is an advantage, since the antibacterial effect of drugs does not affect the normal microflora of the human body. But, on the other hand, the use of bacteriophages requires highly accurate diagnosis of the target pathogen – the causative agent of the disease. Ideally, the selection of phage components of the drug could be done individually for each individual patient. But despite the fact that personalized medicine is much talked about, this concept is too complicated and expensive in practice.

The “weak link” of phage therapy is registration and financial issues. Since the varieties of pathogenic bacteria in the clinical picture are constantly changing, periodic adaptation of the composition of the phage preparation to specific pathogens is required. In the presence of collections of characterized bacteriophages – a kind of “catalog” of phages with a completely decoded genome – this is not difficult to do.

But according to existing rules, with each change in components, it is necessary to re-perform certification actions. It is necessary to develop fundamentally new standards for testing and registration of drugs based on bacteriophages. This is recognized by health professionals, but has not yet been implemented anywhere in the world.