Bacteriophages and antibiotics: instead of or together?

Doctor Virus
The era of antibiotics is coming to an end. Will bacteriophages replace them?Olga Volkova, Ogonek magazine No. 6-2012

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The era of antibiotics is coming to an end. The enormous potential of their impact on microbes is devalued by human frivolity. Now many scientists are pinning their hopes on bacteriophages – natural viruses that destroy bacteria. This medicine is literally lying under our feet.

The sensation came from where they did not expect – from the shores of Antarctica. While Russian polar explorers were drilling a 4-kilometer ice shell over the Antarctic Lake Vostok, trying to get to ancient microorganisms, Swedish researchers from Uppsala University discovered a new type of bacteria in seawater off the coast of the Polar continent. At first glance, these were the bacteria of the most common E. coli that got into the ocean, apparently, together with household waste from the neighboring Chilean station Arturo Prat. And what was unusual about them was that these bacteria are able to easily neutralize the activity of almost all antibiotics known to science.

But that's not all. The bacteria turned out to be from the group of carriers of the beta-lactamase gene, and it, in turn, is part of plasmids – such universal parts that, like elements of the Lego children's designer, can be embedded in the gene structure of any other bacterium. That is, tomorrow this Antarctic bacterium can transfer its invulnerability to antibiotics to all other bacteria. And then humanity will be practically unarmed in the face of the threat of new global pandemics.

Cheap and exclusive

Experts clarify: the threat is far from new. Since the discovery of penicillin, an increasing number of infections have lost sensitivity to antibiotics. Staphylococci, tuberculosis, Pseudomonas aeruginosa, gonorrhea, and many other pathogens adapted to antibiotics have drawn humanity into an endless "arms race" in which primitive organisms oppose science. And medicine, alas, does not always lead in it: every year in the EU countries, about 400 thousand people are infected with antibiotic-resistant infections, and more than 25 thousand die. This "race", it is estimated in Europe, costs at least 1.5 billion euros: about 2 thousand new antibiotics are developed and tested annually in the world.

– However, recently pharmaceutical companies have been reducing funding for such searches because of the economic risk, - the well–known epidemiologist Professor Mikhail Favorov from the International Vaccine Institute at the United Nations tells Ogonka. – Infections adapt too quickly, and the enormous costs of developing new drugs do not have time to pay off.

The World Health Organization calls for strict control of the use of antibiotics and to look for an alternative to them. One of the possible ways is the use of bacteriophages, viruses that destroy half of the bacteria in nature by their own initiative. These nanowires were discovered almost a century ago and shocked the scientific world. Sinclair Lewis, the first Nobel laureate in literature in the United States, even wrote a novel about it, Arrowsmith.

But 10 years later, penicillin was discovered, which turned out to be more effective in fighting microbes. After all, antibiotics are able to destroy whole groups of different microorganisms, and the bacteriophage affects only one. And to treat with a bacteriophage, you can not do without preliminary accurate analyses. Phages could not stand the competition, their research was suspended almost everywhere.

But not in Russia. Our scientists have not stopped researching bacteriophages and using this affordable and inexpensive remedy in surgery, in the treatment of acute intestinal infections, dysbiosis and other ills. Adherents of phage therapy claim: bacteriophages can treat almost all diseases without any restrictions and complications, except those caused by viruses and protozoa.

Now a wave of interest in phages is also rising in the West, although they are not used there for medicinal purposes, but rather for preventive purposes. In the United States, the Food and Drug Administration (FDA) has recognized the safety and appropriateness of phages as dietary supplements that prevent the proliferation of unwanted bacteria on cheeses, fermented dairy products and meat semi–finished products - in short, recommended use as preservatives. In June 2011, the domestic Rospotrebnadzor convened a scientific council, at which a resolution was signed on the introduction of bacteriophages as a new class of food additives.

– Bacteriophages may have good prospects, – says biologist Andrey Aleshkin from the Laboratory of Biology of Bifidobacteria of the Moscow Research Institute of Epidemiology and Microbiology (MNIIEM) named after G.N. Gabrichevsky. – For example, they can also be used to fight persistent nosocomial infections. Staphylococcus aureus is a big problem, including maternity hospitals. You can feed women in labor with antibiotics or endlessly close to the sink, or you can treat surfaces and tools with an aerosol phage, even without violating the regime of the institution. Rospotrebnadzor makes so-called control flushes at food industry enterprises, in children's institutions, hospitals, so the spectrum of bacteria living there is known. And you can choose an effective bacteriophage for it.

The enemy of my enemy

The sacred waters of the Ganges in 1896 interested scientists with their antibacterial effect. British chemist Ernest Hankin managed to obtain an agent from samples of river water that caused the destruction of microbes. In 1917, the French bacteriologist Felix D'Herelle from the Pasteur Institute called these "superagents" bacteriophages – eaters of microbes.

It is already known that a bacteriophage is a virus consisting of DNA and a protein envelope. Like all viruses, it reproduces only in living host cells. At the same time, unlike antibiotics, bacteriophages do not disrupt the normal microflora of the body. They are able to attach only to a single type of microbes, and they do not harm the rest. Having penetrated into the pathogenic cell, the DNA of the phage begins to reproduce its own kind. After multiplying, bacteriophages tear the shell of the host cell and attack other microbes.

First of all, in the 20s of the last century, staphylococcal phage began to treat skin diseases. And Felix D'erelle, as an inspector of the League of Nations health service, used phage therapy in the fight against outbreaks of infectious diseases in the Middle East and India.

At the same time, Georgy Eliava, a Georgian follower of D'erell, with the support of Sergo Ordzhonikidze, People's Commissar of Soviet Heavy Industry, founded the Bacteriophage Research Institute in Tbilisi. The Institute had a large scientific and industrial base with its own clinics, it became the world center for phage therapy of infectious diseases. In 1937, by order of Beria, Georgy Eliava was shot as an enemy of the people, but his institute continued to work until the collapse of the USSR.

– Until 1991, the scientific centers for the development of bacteriophages were Tbilisi and Ufa, – Andrey Aleshkin from the Gabrichevsky State Research Institute reminds Ogonka. – After the collapse of the Union in Russia, drugs were produced independently in several cities, until all manufacturing plants were transferred to the state association of FSUE NPO Microgen, which now owns 13 plants. And if by 2000 bacteriophages were produced by approximately $ 10 million a year, now production has decreased. It's a pity: the market demand for these drugs is much greater than the supply.

Initially, bacteriophages were produced in liquid form. Then tablets with acid-resistant coating, convenient for use and transportation, as well as concentrate, liniment and gel were developed. At the same time, both drugs with one active virus and combined ones (from 2 to 8 types of bacteriophages) are now used in Russia.

– Most often we use bacteriophages for intestinal infection, – says infectious diseases pediatrician Tatiana Moskaleva, who prescribes these drugs to sick children almost daily. – They work well when the causative agent of the disease is known and its sensitivity to phages has been tested. Then the medicine acts directionally, the normal flora is preserved, and there are practically no side effects. I have no complaints except for organoleptic properties – they are too tasteless. Here is a salmonella bacteriophage in tablets – acceptable. And liquid forms have a very unpleasant taste and smell, and this creates difficulties in the treatment of young children.

Doctors recognize that in outbreaks of infections such as pneumonia, they are more likely to prescribe intensive antibiotics to patients. But in some cases, antibiotics are powerless, and it is phages that help. For example, during the rise in the incidence of diphtheria in the 1990s in Russia, many did not get sick themselves, but were carriers of the infection - they lay in the hospital for months without any therapeutic effect. Antibiotics did not work, and bacteriophages came to the rescue. The same situation is now with salmonellosis: those people who do not get sick themselves, but carry bacteria, are more often cured not with antibiotics, but with phages.

Instead of or together

When the microflora is analyzed in the laboratory of the consultative and diagnostic center at the G.N. Gabrichevsky Moscow State Medical Institute and some microbe is found, it is mandatory to conduct tests for the sensitivity of this microbe to both the spectrum of antibiotics and the spectrum of bacteriophages. Bacteriophage should be treated only if bacteria are highly sensitive to it, but even in this case, doctors cannot guarantee a therapeutic effect.

– In the body, everything is not as simple as in a Petri dish from the laboratory, – says Tatiana Moskaleva. – The microbe may be covered with a film, and the bacteriophage will not be able to join it. Or there may be a symbiosis of several microbes, then the reaction will also be different.

Over the long history of phage therapy, Russian research centers have collected a rich database (Western microbiologists are now very interested in it). The largest museum of microorganisms, including phages, is stored in the Scientific Center for the Examination of Medical Products of the Ministry of Health and Social Development of Russia. Thousands of strains of pathogenic bacteria are maintained in a viable state here, viruses have also been bred to them, which are still used for the production of bacteriophage preparations.

– This may be a problem, – says Andrey Alyoshkin. – Phages can destroy only the microbe against which they are bred. Phages, which have been produced in Russia since 1995, are addressed to those strains of bacteria that are stored in the museum. What about modern microbes?

In order to solve this issue, MNIEM established cooperation with the Biofag enterprise in Ufa in 1998. The mechanism was as follows: the Research Institute tested pathogenic bacteria entering the population in the current season for sensitivity to drugs developed at the "Biophage". But after the merger of all phage production plants into one enterprise, this connection was lost.

In principle, the selection of bacteriophages is much simpler and cheaper than the production of new antibiotics. Each type of bacteria has its own phages, and they can be isolated anywhere in the existence of these bacteria: from sewage, feces or soil.

There are, however, arguments against phage therapy, one sounds like this: phages, embedded in the genome of a bacterial cell, can transfer genetic material from one bacterium to another, and this leads to the development of a protective mechanism in microbes.

– Laboratory experiments show that this is possible, but in practice it has not been confirmed in our country, – explains Andrey Aleshkin. – Otherwise, after the application of the bacteriophage, a superinfection with symptoms atypical for this type of pathogen would appear. To exclude this, it is necessary to use phages only after determining their sensitivity to the microflora isolated from the patient. It is necessary to purify drugs from moderate phages, which, having built into the bacterium, do not destroy it, but coexist with it for some time. It is necessary to continue research and exchange data with manufacturers.

Scientists are working on genetically engineered drugs - it is planned to use only phage DNA without a shell to maximize efficiency. They create combined preparations – bacteriophages are combined with bacteriocins (bacterial enzymes), with interferon. And phages are also used in tandem with antibiotics to multiply the chances of victory over the disease.

– It's still too early to give up on antibiotics, - explains Professor Mikhail Favorov. – They will become more and more expensive and less accessible, but they will continue to play a decisive role in the fight against bacteria, perhaps with the participation of auxiliary means, such as bacteriophages. And to develop a scientifically sound strategy for the use of phages in medicine, it would be important to conduct a comprehensive standardized clinical trial of phage-containing medicines. So far, the results of such tests have not been published either here or abroad.

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16.02.2012