Photo from personal archive. Alexander Zharnikov, head of the project office “Development of bacteriophages” at NPO Microgen (Nacimbio holding of the Rostec State Corporation).
Within the framework of the World Week to Combat Antimicrobial Resistance in Bacteria, we spoke with Alexander Zharnikov, head of the project office “Development of bacteriophages” of NPO Microgen (a Nacimbio holding of the Rostec State Corporation) about the problem of antibiotic resistance. the danger of opportunistic bacteria and our habit of taking antibiotics without thinking. Our habits make bacteria immune to drugs, and doctors use bacteriophages only when life is already hanging by a thread. In this case, phages and antibiotics can work together, since they do not interfere with each other.
– The term antibiotic resistance, that is, resistance to antibiotics, has become firmly entrenched in our lives. At what rate does the problem grow and how quickly do bacteria lose sensitivity to antimicrobials?
– Let’s look at the most striking example. Everyone probably already knows the bacteria Staphylococcus aureus, Staphylococcus aureus. How was he defeated at that time? In the 60s of the 20th century, the antibiotic methicillin appeared, which works very well and acts in 100 percent of cases against infections caused by this bacteria. However, in the 90s, methicillin-resistant Staphylococcus aureus bacteria appeared and methicillin stopped working, meaning this antibiotic became useless.
It is being replaced by vancomycin, which successfully combats this bacteria. However, after 10 years, staphylococcus moves from the hospital sector to the outpatient sector and is registered in medical institutions almost everywhere. Vancomycin stops working. This is a clear example of antibiotic resistance, when the time needed for bacteria to adapt to antimicrobial drugs is reduced. At the same time, more and more strains are acquiring forms resistant to antibiotics, which in some cases are almost impossible to combat. In fact, we go back 100 years, when the slightest enteral wound or infection, the slightest dysbacteriosis, can be fatal for a person. And unfortunately there are more and more cases of this type.
In 2001, the World Health Organization adopted a global strategy to curb antimicrobial resistance and several programs for the rational use of antibiotics emerged. This is a very important task, because in the last 30 years not a single molecule, not a single new class of antibiotics has been created in the world that can solve the problem of antibiotic resistance.
– How do bacteria learn to resist antibiotics?
– You can give a simple example. The man went to the hospital, took the subway, visited public places and brought home a type of bacteria. Then perhaps the person will become hypothermic and sick. Antibiotics are started. First, antibiotics destroy bacteria that are sensitive to them, leaving room for those that are not. And it is likely that in each of us and around us there is a large number of strains resistant to antibiotics, but it is the use of antibiotics that shifts this balance towards resistant strains, that is, increasing their number.
The World Health Organization makes dire predictions: within 10 to 20 years, no existing antibiotics will be active against antibiotic-resistant strains.
– You named Staphylococcus aureus… What other infections are becoming more dangerous due to antibiotic resistance?
– Unfortunately, even those that are constantly present in our microbiota are the so-called opportunistic pathogens. Any immunodeficiency condition can upset the balance and opportunistic pathogens can cause disease. For example, any intestinal infection causes a change in the balance of the intestinal microbiota and the proliferation of opportunistic bacteria, which at this time become extremely dangerous. And if the microbiome contains strains resistant to antimicrobial drugs, the situation becomes doubly dangerous.
Today, among the most common opportunistic microorganisms, several well-known bacteria prevail: Escherichia coli (Escherichia coli), Klebsiella, staphylococcus and streptococcus. These infections are characterized by a chronic course of the disease with periodic exacerbations. If the pathogen proves resistant, therapy is delayed and the patient undergoes several treatments with different antibiotics. This, of course, does not have the best effect on human health.
The WHO clearly recognizes that nosocomial infections are the most dangerous; It is these strains that mutate with greater frequency and activity.
– We know what bacteriophages are from a school biology course: viruses that can destroy bacteria. What is your contribution to solving the problem of antibiotic resistance?
– A bacteriophage is the same ancient creature as a bacteria, they are millions of years old. According to some data, this is the most numerous species on Earth, there are 10 to the power of 32, they are always close to bacteria and their genetic function is to regulate the bacterial balance on our planet. The bacteriophage works in a very simple way. It finds a bacteria and, if it is suitable in appearance and sensitivity, destroys it: it penetrates its interior and begins the process of replicating its DNA. During the copying process, new bacteriophages appear, tearing apart the bacteria from the inside and continuing their work. This is how the natural regulation of the balance of bacteria on Earth occurs and, in fact, in the human body bacteriophages and bacteria behave in exactly the same way.
– What does “appropriate in appearance” mean?
– This suggests that bacteriophages are very specific. For example, the Escherichia coli bacteriophage infects and destroys only Escherichia coli bacteria, and no others.
– What about tuberculosis?
– There have been many attempts, both in Russia and in the world, to find and produce a bacteriophage against Mycobacterium tuberculosis in the required quality and in sufficient quantity, but so far there is nothing special to boast about. Mycobacteria have a number of properties that are very different from ordinary, familiar bacteria. In theory, this is still possible, but in the future.
– How do bacteriophages manifest themselves in the fight against nosocomial infections?
– The same as against any other bacteria. If there is a bacteriophage sensitive to nosocomial infection, it will definitely work.
– Everyone knows the anti-vaccines. Lately, even a whole category of people has appeared who fear the use of phages because, according to them, they do not want foreign DNA to enter the body. Is this fear justified?
– This point of view is ridiculously absurd. First of all, bacteriophages, along with bacteria, are always present in our body. And not just in our body: they are everywhere! Their DNA is not foreign to us. This is evolutionary DNA and cannot cause any harm to the body. Furthermore, the drugs produced by our company use only natural virulent bacteriophages, that is, those that we find in the environment. Your selection is a great selection job. But we did not perform any genetic transformation with bacteriophages. The preparations contain only what actually exists in nature, and this is exactly what the body needs in each specific case in relation to each specific bacteria.
– Nowadays, antibiotics and bacteriophages are usually opposites. Antibiotics don’t work, so we try bacteriophages. Can antibiotics and bacteriophages work together?
– First of all, it must be said that bacteriophages are a legacy of the Soviet Union. In the USSR, bacteriophages were actively used, and with the advent of antibiotics, fortunately, their production and use did not stop. As I already said, in the last 30 years not a single new antibiotic has been created in the world that could radically change the existing situation with antibiotic resistance, and all programs (to combat antibiotic resistance – ed. ) that operate today aim at the rational use of existing antibacterial drugs. Another factor that must be mentioned when answering this question is doctors’ lack of knowledge about bacteriophages.
It is neither right nor correct to say that bacteriophages are an alternative to antibiotics. This is an additional tool for doctors in the fight against antibiotic-resistant strains. Phages can be used both as monotherapy and in conjunction with antibiotics. Sharing does not pose any additional risk, this has been proven for a long time. But, unfortunately, most often doctors turn to bacteriophages only when the patient’s condition becomes life-threatening, when the prospect of sepsis and amputation of a limb has already arisen. This, of course, is very sad, but there are many such cases.
– Do you remember a case when antibiotics did not help, but phages coped with “superbugs”?
– I will not list specific cases, there are quite a few. One of the Moscow institutes is currently conducting a pilot study on postoperative diabetic foot sanitation with phages against the background of multidrug-resistant strains. Another institute is conducting a pilot study on the use of bacteriophages against urological strains that cause cystitis. There are more and more examples of this type. We try to inform doctors as actively as possible so that they turn to bacteriophages in the early stages of the disease. And this work is bearing fruit: doctors and patients are increasingly turning to us.
In January 2020, we created a biological resource center that is dedicated to massive and global selection of bacteriophages, monitors the bacterial landscape of the Russian Federation and tries to create effective drugs.
– How do you evaluate the potential for future studies of bacteriophages?
– New bacteriophage preparations and new dosage forms are being developed. The spectrum of already existing phages covers approximately 86% of the entire bacterial landscape of opportunistic bacteria. Our task is to bring it to 92%.
The investigation continues. We have global personalized medicine programs, but this is a matter of the distant future.
– Will medicine be able to create a “cocktail” of bacteriophages based on the patient’s set of bacterial strains?
– Yes, in theory this has already been demonstrated many times. This method is already used in some parts of the world, for example, within the framework of compassionate medicine in Europe and within the “right to try” framework in the United States. When all methods to combat the infection have been exhausted, personalized phage cocktails are created. They are almost 100% likely to work against a specific bacteria, since they select for that specific bacteria.
– As you know, most bacteria, including opportunistic ones, do not live in the body alone, but as part of so-called biofilms. And this is one of the key protective factors of bacteria that ensures resistance to antibiotics. Can bacteriophages overcome this protective barrier?
– Yes, bacteriophages are capable of destroying biofilms. Many scientific works have been written on this topic.
– Where and how do they look for bacteriophages? Logically, they should be somewhere near the bacteria…
– In fact, bacteriophages are always close to “their” bacteria. We remember from history that in the late 90s of the 19th century, the English biologist Ernest Hankin, who was working in India analyzing water samples from the Jumna River, a tributary of the Ganges, drew attention to the fact that in a section of the river in a milliliter of water there were a large number of cholera vibrios, and in the samples taken downstream they practically do not exist. He then suggested that the water might contain some type of bacterial infecting agent. Twenty years later, the French biologist Felix d’Herelle would isolate it and call it bacteriophage… Bacteria are always accompanied by bacteriophages, which, as he said, regulate their number, maintaining balance in nature. Consequently, any place where bacteria live is suitable for searching for phages: sewage, puddles and natural water bodies: rivers and lakes. But it is important to understand that this search is quite global and extremely complex, since it is not enough to find a bacteriophage and isolate it from the natural environment. Before entering the drug, bacteriophages go through a long selection and research process. Our preparations contain only virulent bacteriophages, those that, when they encounter a bacteria, introduce their DNA into it, actively replicate and break the bacteria, causing its death. Along with them, moderate bacteriophages are also found. Their genetic code is such that, in fact, they partially integrate their genome into the genome of the bacteria and coexist with it. From our point of view, this is a harmful property that teaches the bacteria to resist bacteriophages. We work only with virulent bacteriophages that destroy bacteria. Obtaining a phage of this type is a very complex process.
-What would you say to those who take antibiotics without thinking?
– Those who self-medicate accelerate the development of resistance to antibiotics. I would encourage all patients to strictly follow their doctors’ orders, and I would encourage doctors to exercise restraint and seriousness when prescribing antibiotics. A person should not be prescribed an antibiotic, a bacteriophage or any drug.
THE NAIS IS OFFICIAL EDITOR ON NAIS NEWS