The Apocalypse is canceled
Insects will save us
The main saviors of human civilization today and, especially tomorrow, are small six–legged animals, rummaging through garbage and carrion. At first glance, it doesn't seem too real and attractive, but, nevertheless, it is.
At the XV Congress of the Russian Entomological Society, held in Novosibirsk, the head of the Laboratory of Biopharmacology and Immunology of insects of St. Petersburg State University, Doctor of Biological Sciences Sergey Ivanovich Chernysh told about how scavenging insects living in the midst of microbes and feeding on human waste, manage to thrive and remain invulnerable to bacterial attacks. A complex of antimicrobial peptides synthesized by insects can solve a global medical problem – the resistance of various pathogens to antibiotics.
In the apocalyptic films "Armageddon" or "Independence Day", the end of the world seems to be something sudden and came from outside. But so far, we are in danger of a much more real danger than an alien attack or the fall of a giant meteorite: the ubiquitous pathogenic bacteria are "getting smarter" every year, increasing protection against not so rapidly changing drugs:
– In the middle of the last century, with the advent of antibiotics, humanity had a feeling that there would be no problems with bacteria. But by the end of the century, the situation has changed significantly and continues to change every day: bacteria were not as simple as one might think. They have found effective and wonderful ways to survive in an environment saturated with antibiotics – they have developed resistance. This problem has been declared by the World Health Organization as the number one problem for medicine of the present and, in particular, of the future. The wave of antibiotic-resistant unicellular organisms that covers human civilization throughout the globe is becoming more and more. Not only is each individual bacterium fighting for its life, they accumulate this experience, form a "resistome" – a complex of protective mechanisms that microorganisms "bequeath" to descendants and, more importantly, horizontally transmit to their neighbors," said Sergey Chernysh.
Against the background of this terrible scenario, insects that have been in contact with human ancestors for hundreds of millions of years and devouring human waste, and often human corpses, all the time that our civilization has existed, seem invulnerable. The substances that their immune system produces have passed the test of time and are winning the fight against microorganisms. The staff of the Laboratory of Biopharmacology and Immunology of Insects of St. Petersburg State University took up the solution of this successful strategy.
– Our interest is connected with the study of the immune system of insects, we have "processed" about two hundred species primarily from the point of view of benefits for medicine. First of all, the structures of antimicrobial peptides were studied. As a result, we settled on one group of insects – synanthropic diptera-saprophages. Synanthropic (ecologically related to human settlements) are in priority precisely because they have direct contact with the human microflora – they and we have a common bacterial enemy. Secondly, saprophages live in an environment that is maximally saturated with all kinds of microflora: these are corpses, excrement, and in some cases wounds. In short, all those conditions where bacteria pose the most immediate threat to life, including the larvae of diptera. As a result, the latter have an extremely powerful immune system, if compared with other insects. The system is quite complicated, but the most important thing in it for us is that, recognizing the pathogen, the cells of the fatty body of the larvae begin to produce antimicrobial peptides in huge quantities exceeding those that we were able to observe in other insects, – said Sergey Chernysh.
To date, about 2,500 antimicrobial peptides have been isolated from all groups of living organisms, about half of them belong to insects and fit into four large groups: defensins, cecropins, diptericins and P-peptides (proline-rich peptides).
In each group of insects there are either one or two, sometimes more forms of antimicrobial peptides. Sergey Chernysh and his colleagues work with the larvae of the blue meat fly Calliphora vicina (simply maggots), which have concentrated all the variety of peptides characteristic of the insect class as a whole. The larvae synthesize all four groups of compounds within a few hours after they have received a "charge" of bacteria. They accumulate life-saving substances in the hemolymph ("blood" of insects), forming a single complex, and its properties are not reducible to the characteristics of individual components. This is one of the secrets of the antibacterial "shield" of insects.
In contrast to such a multicomponent approach, the principle of monotherapy operates in medicine and pharmacology, at least in relation to infectious diseases.
– When you come to the doctor with a bacterial problem, he prescribes you one antibiotic, if the medicine does not help – another, then maybe a third. But if this is to no avail, your business is bad, because there is no more complex combination in science. The doctor, of course, can prescribe five antibiotics at once, but it will be completely scientifically unjustified, and the result is unknown. The principle of monotherapy is transferred to the development of new drugs, and the problem is that the result is temporary. By introducing a separate factor into the environment of bacteria, albeit a very powerful one that causes rapid selection in them, you inevitably provoke an increase in resistance, and nothing can be done about it today," the researcher continued.
Insects use not one, not two, not four, but incomparably more substances at the same time, and the main opportunity that these complexes open up is their evolutionary stability. Obviously, nature has not wasted time – almost half a billion years – and energy to create such a complex system.
The effectiveness of the antibacterial complex synthesized by maggots is illustrated by a relatively simple experiment: growing a culture of bacteria in the presence of an antibiotic, for example meropenem – a "record holder" in the fight against gram-negative bacteria.
– It turned out that if the bacterium is diligently poisoned, with each passage (sequential replanting of the culture of microorganisms) raising the concentration of the antibiotic, the resistance of the microorganisms will change. After about 13 passages, a bacterium will appear that has significantly greater resistance to meropenem than its predecessors. And after about 20 generations, it will become absolutely invulnerable – the impact is no longer possible. It will be impossible to treat even earlier, because you cannot prescribe medicines to a person instead of one pill, for example, sixty, he simply will not swallow them," commented Sergey Chernysh.
Against this frightening background, the effectiveness of an antimicrobial insect complex of 15 different peptides adapted to joint action during evolution looks fantastic:
– No matter how much we influence the peptide complex on a bacterium, for example, E. coli or related enterobacteria, there is no change in resistance to it. If the microorganisms were sensitive to the drug at a certain level, then this susceptibility persists, regardless of the number of generations. We tested it on 250 generations – this is a solid period in evolutionary and historical terms," the scientist added.
However, the fight against bacteria is not just a battle with brainless unicellular, which only during breeding become resistant to the damaging factor. No, they are able to unite and resist attacks from outside almost immediately:
– Once in the host organism, bacteria very quickly transition into a biofilm state: a kind of multicellular community, which may include not one, but several types of bacteria, and they produce a certain set of compounds, which is called a matrix. They cover bacteria like a blanket, protecting themselves both from attacks by immune system cells and from antibiotics. To date, biofilms are the source of most bacterial diseases in humans (more than 80%), animals and, perhaps, plants. These are the most complex diseases – chronic infections, – said Sergey Chernysh.
Moreover, many diseases that we used to consider non–infectious are caused by biofilms - plaques in blood vessels, atherosclerosis, myocardial inflammation. The situation is similar with oncological diseases: many of them are bacterial in nature. Of course, cancer is a disease associated with some mutations or the introduction of viral oncogenes into the genome, causing the appearance of pathologically altered cells. But in order for such cells to take root in the body, they need a certain environment: an inflamed area that has arisen due to bacterial biofilms is ideal. Another place of accumulation of such infections is diabetic ulcers: every year more than one million amputations of the lower extremities are carried out in the world due to complications of diabetes, this is more than losses in military conflicts and terrorist acts.
An extensive study conducted by the staff of the Laboratory of Biopharmacology and Immunology of St. Petersburg State University showed that it is very difficult or impossible to get rid of bacterial biofilms with an antibiotic. Even if the antibiotic destroys the bulk of the bacteria, there is a high probability that the survivors will quickly restore the population and it will already be less sensitive to the antibiotic (the strongest survive!). However, if you use a drug, for example, the already mentioned meropenem, in combination with a complex of antimicrobial peptides FLIP7, you can completely destroy the population of biofilm bacteria, thus preventing the development of chronic infection.
Research has already led to the creation of a new generation of medicines based on peptides of the insect immune system. The first-born in this series was Allokin–alpha, an antiviral drug based on the peptide alloferon, obtained by chemical synthesis. For the first time, alloferon was obtained by the staff of the Laboratory of Biopharmacology and Immunology of St. Petersburg State University from the hemolymph of larvae of the same maggot. To date, more than two million patients with papilloma-viral, herpetic infections, moderate forms of hepatitis B have been treated with Allokin-alpha. In the future, the Entomix gel, an antibiotic film coating based on a complex of antimicrobial peptides FLIP7, has an even wider scope of medical use. The original technology of parallel biosynthesis of peptides in the eukaryotic system (insect larvae) is used in the production of FLIP7, the development of which is supported by a grant from the Russian Science Foundation. FLIP7 can be independently used to treat various forms of biofilm infections resistant to known drugs. At the same time, it is not necessary to consider it as an alternative to traditional antibiotic therapy. Studies have established that FLIP7 serves as a powerful synergist of many vital groups of antibiotics (carbapenems, aminoglycosides, cephalosporins, glycopeptides, etc.), allowing hundreds or even thousands of times to reduce their effective dose necessary for complete suppression of infection.
The antitumor and antiviral drug Allostatin, which has shown good results in the fight against cancer in laboratory mice, has passed the stage of preclinical trials:
– We hope that Allostatin and its analogues will allow us to advance in the treatment of oncology, and maybe at the next congress I will be able to say that another drug has appeared in pharmacies," commented Sergey Chernysh.
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29.08.2017