What are antibiotics?

In 1896, Gosio (V. Gosio) isolated from the mold (Penicillium) the first crystalline antibiotic - mycofenic acid - and showed that this compound retarded the development of anthrax bacteria. In 1924, Gratia and Date (A. Gratia, S. Dath) described a new antibiotic substance formed by Actinomyces albus, which they called actinomycetin. In 1931, the antibiotic citrinin was isolated from a culture of Penicillium citrinum.

A milestone in antibiotic research is the work of Dubos (R. J. Dubos, 1939), who obtained from the soil bacterium Bacillus brevis the crystalline substance tyrothricin, consisting of two antibiotic polypeptides - gramicidin and tyrocidin.

Gramicidin was more active against gram-positive, and thyrocidin - against gram-negative bacteria. Tyrothricin has a strong bactericidal effect in vitro against many pathogenic microbes, providing a curative effect in experiments on mice infected with pneumococcus. This is the first antibiotic actually introduced into medical practice; it is widely used today. Later, in 1942, G. F. Gause and M. G. Brazhnikova isolated an antibiotic from a new variety of Bacillus brevis called gramicidin C, which has some advantages over Dubos tyrothricin.

The revolution in the doctrine of antibiotics occurred as a result of the discovery by A. Fleming of penicillin. Back in 1929, Fleming observed that around the colonies of Penicillium notatum, the colonies of staphylococcus in a cup were petrilized, and the filtrates of the broth cultures of this fungus had an antibacterial effect against gram-positive and some gram-negative microbes (gonococci, meningococci). Fleming failed to isolate pure penicillin from a culture of Penicillium notatum due to the low stability of this antibiotic. In 1940, Florey and Chain (H. W. Florey, E. B. Chain) developed a method for extracting penicillin from the culture fluid of Penicillium notatum, and the high therapeutic activity of this drug was soon revealed.

Classification of antibiotics

There are three main principles on the basis of which antibiotics can be classified: 1) according to the spectrum of action, that is, according to the nature of the biological object in relation to which this antibiotic is active; 2) according to the chemical structure of the antibiotic; 3) according to the molecular mechanism of the action of the antibiotic on the cell.

Classification of antibiotics by spectrum of action

The antibiotic is usually divided into antibacterial, antifungal and antitumor. For medical practice, such a division is convenient, as it indicates the possible scope of this drug. In fact, such a subdivision has many significant drawbacks, because even antibiotics that are close to each other can differ greatly from each other in their antibacterial spectrum of action. Antibiotics from the penicillin group can serve as examples: some inhibit the development of only gram-positive microbes, others - both gram-positive and gram-negative microbes.

Antibacterial antibiotics inhibit the development of bacteria. Some of them, for example, benzyl penicillin, macrolides, ristomycin (ristocetin, spontin), novobiocin and others, are active mainly against gram-positive microbes, others, such as polymyxin, inhibit the development of mainly gram-negative bacteria, others, for example, tetracyclines, levomycetin (chloramphenicol, chloromycetin), aminoglucosides (streptomycin, monomycin, kanamycin, neomycin and gentamicin), the so-called broad-spectrum antibiotics, inhibit the growth of both many gram-positive and gram-negative bacteria.

Antifungal antibiotics have a specific inhibitory effect on the growth of fungi. The antibiotics nystatin and levorin, which are used to treat candidiasis and other diseases caused by yeast-like fungi, have found wide application in medical practice. The antibiotic amphotericin B is used to treat generalized and deep mycoses. These three drugs belong to the group of polyene antibiotics. Of the antifungal antibiotics of a non-polyene structure, griseofulvin turned out to be a very effective therapeutic agent.

Antitumor antibiotics. It has been established that some antibiotics inhibit the development of not only bacteria and fungi, but can also delay the reproduction of malignant tumor cells. Some of these drugs have found application in medical practice.

Antitumor antibiotics include six groups of chem. compounds, representatives of which are used in the clinic.

The first group consists of actinomycins discovered in 1940. Due to their high toxicity, they did not attract attention for a long time. Only in 1952, in experiments on animals with transplanted tumors, it was found that actinomycins inhibit the development of many transplanted tumors. In the clinic, actinomycins are mainly used to treat adenocarcinoma of the kidney or Wilms' tumor in children.

The second group of antitumor antibiotics are anthracycline antibiotics. The most important representative of this group - rubomycin - is one of the main drugs for the treatment of uterine chorionepithelioma and acute leukemia. Rubomycin in these serious diseases often leads to clinical recovery.

The third group of antitumor antibiotics consists of aureolic acid derivatives. The antibiotic olivomycin belonging to this group is mainly used to treat testicular tumors, including seminomas, teratoblastomas and embryonic cancers in the generalized stage with metastases to the lungs, abdominal organs and lymph nodes. Another important indication for the use of olivomycin is tonsillar, rapidly metastasizing tumors of the nasopharynx.

Classification of antibiotics by chemical structure

Classification of antibiotics by chemical structure is more rational. It allows you to compare the structure of antibiotics with the mechanism of their antimicrobial action, side effects and excretion processes from the body. Antibiotics belong to different groups of chemical compounds. The acyclic antibiotic group includes full-body antibiotics, including nystatin, amphotericin B, trichomycin, candicidin, etc. Another group includes antibiotics of the tetracycline structure - see Tetracyclines. Hygromycin, used in veterinary medicine as an anthelmintic agent, belongs to aromatic antibiotics. The group of oxygen-containing heterocyclic antibiotics includes the antifungal antibiotic griseofulvin, which is widely used in dermatology, as well as the antibacterial antibiotic novobiocin, which is active against gram-positive cocci. Antibiotics Macrolides having in their molecule a macrocyclic lactone ring associated with one or more carbohydrate residues are allocated to a separate group (see Macrolides).

This group includes a number of medically important antibiotics: erythromycin, oleandomycin, etc. The antibacterial antibiotic lincomycin is close to macrolides. Rubomycin is an anthracycline antibiotic. The group of aminoglycoside antibiotics, built from the residues of aminocyclites and carbohydrates, includes streptomycin and its derivatives (see Streptomycins), neomycin, kanamycin, monomycin and gentamicin. A separate group includes penicillins, the most widely used in medical practice (see Penicillins). Antibiotic polypeptides or proteins include gramicidins, tyrothricins, bacitracin, polymyxins, lysozymes, viomycin (florimycin), colicins, etc. Iron-containing polypeptides include the antibiotic albumicin. A rather homogeneous group is made up of actinomycin antibiotics, which have antitumor activity (see Actinomycins). Finally, the last group includes numerous streptothricin antibiotics, which, due to their high toxicity, have not found application in medical practice. Attempts are being made to use some antibiotics from this group in agriculture.

Classification of antibiotics according to the molecular mechanism of action

The most important antibiotics for medical practice can be divided into several groups: 1) affecting the synthesis of the bacterial cell membrane (Penicillins, ristomycin, vancomycin, novobiocin, D-cycloserine, etc.); 2) disrupting the synthesis of proteins in a bacterial cell (antibiotics of the tetracycline structure, macrolides, chloramphenicol, etc.); 3) suppressing the synthesis of proteins in a bacterial cell and at the same time disrupting the reading of the genetic code during translation (aminoglycosides); 4) inhibiting the synthesis of nucleic acids in cells (rifamycins, antitumor antibiotics); 5) violating the integrity of the cytoplasmic membrane in fungal cells (antifungal antibiotics Polyenes).

Semi-synthetic antibiotics

After the chemical structure of most antibiotics was elucidated, attempts were made to carry out the chemical synthesis of antibiotics. The synthesis of levomycetin turned out to be successful, and at present, it is prepared exclusively by chemical means. Although the synthesis of some other antibiotics turned out to be possible (penicillin, gramicidin, etc.), in practice, obtaining them with the help of producer microorganisms is simpler and more economical than obtaining them by chemical synthesis.

Initially, antibiotics were used in the form in which they were synthesized by microorganisms. However, as the chemistry of antibiotics developed, methods were developed to improve the properties of natural antibiotics by partially changing their chemical structure. In this way, the so-called semi-synthetic antibiotics were obtained, in which the main nucleus of the original native antibiotic molecule is retained, but some radicals of the molecule are replaced by others or removed. Particularly great progress has been made in obtaining semi-synthetic penicillins (see Penicillins, semi-synthetic).

It was shown that the core of the penicillin molecule is 6-aminopenicillanic acid (6-APA), which has a weak antibacterial activity. When attached to the 6-APK molecule of the benzyl group, benzylpenicillin is obtained, which is currently produced in the factories of the medical industry and is widely used in honey. practice called penicillin. Benzylpenicillin has a significantly higher antibacterial activity than 6-APA. However, benzylpenicillin, along with a very powerful chemotherapeutic activity and low toxicity, also has some disadvantages: it is active mainly against gram-positive microbes, it is easily destroyed by the enzyme penicillinase, which is formed by some microorganisms, which are therefore resistant to its action.

Especially often among pathogenic bacteria, penicillinase producers are staphylococci. Most penicillin-resistant staphylococci isolated in the clinic form penicillinase. In addition, benzyl-penicillin quickly loses its activity in acidic and alkaline environments and is therefore destroyed in the gastrointestinal tract. The benzyl residue can be separated from the benzylpenicillin molecule and replaced by the rest of the molecule of another organic compound.

Hundreds of different semi-synthetic penicillins (derivatives of 6-APA) have been obtained in this way. Most of them are of less interest than the original benzylpenicillin. But some of the resulting semi-synthetic penicillins were found to be resistant to the action of penicillinase, such as methicillin, which is also effective in the treatment of infections caused by benzylpenicillin-resistant staphylococci. Other semi-synthetic penicillins resistant to penicillinase proved to be resistant to acidic environments (oxacillin). Drugs of this type can be administered orally. There are semi-synthetic penicillins with a much broader spectrum of antibacterial activity than the original benzyl-penicillin, which retard the growth of many gram-negative microbes (ampicillin).

Among tetracycline antibiotics, derivatives were obtained that are excreted from the body much more slowly, and therefore their therapeutic dosages are 5–10 times less than the dosages of the original natural tetracyclines. From the antibiotics rifomycin SV, a derivative of rifampicin was obtained - an effective anti-tuberculosis drug, which, moreover, is much more active against gram-negative bacteria than the original rifomycin SV. New semi-synthetic derivatives of lincomycin, chloramphenicol, etc. were obtained.

Use of antibiotics

Antibiotics are very widely used in medical practice for the treatment of various bacterial, fungal infections and some tumors. Rational use of antibiotics is based on accurate knowledge of their pharmacological and chemotherapeutic properties.

The success of antimicrobial antibiotic therapy primarily depends on the sensitivity of the pathogen to the drug used, the form of the pathological process, the phase of the disease and the state of the body's defense mechanisms. When prescribing antimicrobial antibiotics, it is necessary, given the sensitivity of the pathogen to the antibiotic, to prescribe the most active of them, if possible. In chronic diseases, it is advisable to determine the sensitivity of the pathogen to the antibiotic in vitro every 10-15 days of treatment. In the case of severe diseases, when treatment needs to be started as soon as possible, broad-spectrum antibiotics are usually prescribed. The final treatment is prescribed after determining the sensitivity of the pathogen to the antibiotic.

Doses of antibiotics should be prescribed in such a way as to achieve antibacterial concentration in the lesions. Most antibiotics are rapidly excreted, and therefore, to maintain an effective concentration of the drug in the body, the antibiotic is usually administered to the patient several times a day, depending on the rate of their release.

The success of treatment is harmed by the emergence of resistant forms of microbes. To prevent the emergence of resistant forms of pathogens, the simultaneous use of two or more antibacterial drugs with different mechanisms of action is recommended, since resistance in the pathogen develops much more slowly to two antibiotics with different mechanisms of action than to one drug. The following combinations of antibiotics have proven themselves in the clinic: tetracycline with macrolide antibiotics - oleandomycin (oletethrin) or erythromycin, penicillin with streptomycin (in the treatment of acute infections, but not tuberculosis). An antibiotic is successfully combined with synthetic chemotherapeutic drugs, for example, for the treatment of tuberculosis, streptomycin is usually prescribed simultaneously with isoniazid (isonicotinic acid hydrazide) and para-aminosalicylic acid (PAS). In acute diseases, antibiotics and sulfa drugs are often prescribed. It is not recommended to simultaneously prescribe antibiotics that act on dividing cells (penicillin) and bacteriostatic antibiotics (tetracyclines), since under the influence of the latter, cell division is suspended and penicillin loses its activity. Antitumor antibiotics are prescribed in clinics only according to strictly established indications for each drug.

Antibiotics are not substances indifferent to the body and, having a high therapeutic activity, can cause a number of more or less severe adverse reactions. Convalescents who received antibiotics during the illness have less strained immunity than convalescents who did not receive antibiotics. Relapses of the disease are observed more often in those recovering from typhoid fever who received chloramphenicol during the acute period of the disease than in those recovering who did not receive this antibiotic. Therefore, sometimes antibiotic therapy is combined with vaccine therapy, especially in typhoid fever. Antitumor antibiotics by themselves greatly inhibit immunogenesis.

Often, antibiotics cause various complications of an allergic nature, limited and generalized skin lesions (see Toxidermia), Quincke's edema, vasomotor rhinitis and arthralgia. Usually the first precursor of allergic reactions is eosinophilia. Immediately after the administration of an antibiotic, anaphylactic shock can be observed (see), especially after the administration of penicillin and much less often after the administration of streptomycin. Therefore, when using penicillin, especially in patients who have previously received it, skin tests for sensitivity to penicillin should be performed. Although skin tests do not always reveal hypersensitivity to penicillin, they nevertheless allow some patients to avoid severe allergic reactions.

One of the most commonly observed complications with antibiotic use is superinfection or secondary infection. The use of an antibiotic leads to the disappearance of saprophytic microorganisms sensitive to them from the body. Instead, conditionally pathogenic bacteria and fungi resistant to antibiotics begin to multiply in the body: E. coli, Proteus, staphylococci, yeast-like fungi, etc., which, under certain conditions, can cause the development of a more or less severe secondary infection. Resistant staphylococci that develop after taking tetracyclines sometimes cause severe enterocolitis, yeast-like fungi often lead to the development of local lesions (on the mucous membranes), less often - generalized diseases

The destruction of normal intestinal microflora under the influence of antibiotics sometimes leads to beriberi, since intestinal bacteria are producers of vitamins of group B and partly of group K. Therefore, with prolonged use of antibiotics, it is recommended to prescribe multivitamins and, in particular, vitamins of group B simultaneously with antibiotics.

Antibiotics can also have a direct toxic effect on the body; for example, aminoglycosides selectively affect the VIII pair of cranial nerves and cause vestibular disorders or irreversible deafness; some of them are more likely to cause vestibular disorders (streptomycin, gentamicin), while others (neomycin, monomycin, kanamycin, dehydrostreptomycin) lead to irreversible deafness if administered incorrectly. Of particular danger in this regard is neomycin, which therefore should not be used parenterally. It is also impossible to prescribe two aminoglycoside antibiotics at the same time or use one aminoglycoside immediately after stopping the administration of another member of this group. Antibiotics Macrolides and tetracyclines in large doses can cause liver damage, and levomycetin, although very rarely, affects hematopoiesis and leads to irreversible bone marrow aplasia. Anticancer antibiotics cause many adverse reactions, the most severe of which are associated with disorders of the gastrointestinal tract and oppression of hematopoiesis.

Given the possibility of severe adverse reactions caused by antibiotics, their use should always be carried out under close medical supervision.

Bacterial resistance to antibiotics

The widespread introduction of antibiotics into practical medicine and veterinary medicine has led to the spread of antibiotic-resistant bacteria. Such bacteria can be divided into two groups: 1) resistant to one antibiotic and 2) resistant to several antibiotics simultaneously (multiple resistance). Bacteria of the first group can be resistant to several antibiotics, if the latter are characterized by close chem. structure and unambiguous mechanism of action on the bacterial cell (cross-resistance). For example, bacteria resistant to the action of rifamycin are simultaneously resistant to streptovaricin due to the common mechanism of action for these drugs associated with impaired RNA polymerase function. Resistance to streptomycin is combined with resistance to dihydrostreptomycin and, partially, to neomycin, that is, the object of action for all these antibiotics are proteins in the 30 S-subunit of the ribosome.

Genetic control of the level of sensitivity to antibiotics is determined by genes localized in bacterial chromosomes or in transmissible plasmids. The latter provide multiple cell resistance to several antibiotics.

A bacterium resistant to this antibiotic is a mutant in the corresponding chromosomal gene that controls the structure of the cell components that are the object of antibiotic action. Mutations in chromosomal genes leading to antibiotic resistance occur with a low frequency, ranging from 10-6 to 10-12. Therefore, the occurrence of simultaneous chromosomal mutations to two or more antibiotics is almost impossible. Bacteria carrying chromosomal mutations for two or more antibiotics result from an independent mutation in a strain that is primarily resistant to one of the antibiotics.

The molecular mechanism underlying the resistance of a mutant bacterium is different for different antibiotics and is determined by damage to the cell structures that interact with these antibiotics. Studies by Gorini, Kataya, Traub and Nomura (L. Gorini, E. Kataja, 1964; P. Traub, M. Nomura, 1968) showed that streptomycin inactivates the 30 S-subunit of the ribosome due to interaction with the 10 protein included in its structure, as a result of which the translation of genetic information is disrupted and the synthesis of the polypeptide chain is distorted. A mutation in the str A gene leads to a change in the structure of the 10th protein, as a result of which the latter loses its ability to interact with antibiotics. From the works of Heil and Zillig (A. Heil, W. Zillig, 1970) another example of antibiotic resistance is known, which is also associated with a mutational change in the cell substrate that is the object of antibiotic action. Bacteria resistant to rifamycin, an antibiotic that inactivates RNA polymerase, contain an enzyme that is insensitive to this antibiotic due to the altered subunit of the enzyme, as a result of which the complex of the RNA polymerase molecule with rifamycin is not formed. Another mechanism that ensures bacterial resistance to antibiotics is a violation of the process of its penetration into the cell and accumulation in it. Gram-negative bacteria are resistant to the action of actinomycin due to its inability to penetrate the cell wall. Treatment of these bacteria with ethylenediaminetetraacetic acid (EDTA) increases their sensitivity to antibiotics. Bacterial mutants resistant to EDTA and simultaneously resistant to actinomycin were obtained. Research by Reeve and Bishop (C. Reewe, E. Bishop, 1965) showed that bacterial resistance to chloramphenicol (levomycetin), resulting from mutations in the chromosome, is also associated with a violation of the permeability of the bacterial membrane for this antibiotic.

The enzymatic mechanism of resistance to antibiotics is widespread in the world of bacteria. It consists in the transformation of an active antibiotic into an inactive form as a result of the action of modifying cell enzymes on it. This type of resistance is controlled mainly by R-plasmids carrying various combinations of resistance genes to the following antibiotics: ampicillin, chloramphenicol, kanamycin, streptomycin, spectinomycin, gentamicin, and tetracycline. Probably, plasmid-controlled bacterial resistance is not limited to the listed antibiotics, the list of which is constantly growing as new R-factors are discovered and new antibiotic preparations are created. Resistance determined by R-plasmids is common among bacteria belonging to different genera and families: Shigella, Escherichia, Salmonella, Proleus, Pseudomonas, Staphylococcus. The molecular mechanisms responsible for the resistance of R-factor-bearing bacteria (R+ cells) to different antibiotics are different. Penicillin resistance is associated with the synthesis of penicillinase (ß-lactamase), controlled by one of the R-factor genes. This enzyme hydrolyzes the ß-lactam ring of penicillin. Sawai (T. Sawai, 1970) and co-authors found that there are three types of penicillinases that differ from each other in physicochemical, enzymatic and immunological properties. Along with plasmid-specific penicillinases, bacteria have been found to contain penicillinases whose synthesis is controlled by chromosomal genes. They are able to inactivate all known derivatives of penicillin and cephalosporin.

Deciphering the biochemical and genetic mechanisms that ensure bacterial resistance to antibiotics substantiates the rationality of their clinical use, ways to overcome bacterial resistance, and the direction of the search for new therapeutic drugs. The overcoming of multiple antibiotic resistance in bacteria can theoretically be achieved by using drugs that selectively block R-factor replication (drugs of the acridine series) or by inactivating antibiotic-modifying enzymes. One of the possible approaches to combat antibiotic resistance associated with the action of R-enzymes is the combined use of drugs, some of which protect others from inactivation. For example, gentamicin is capable of inhibiting the inactivation of other aminoglycosides at low concentrations. From the works of Umezawa (H. Umezawa) it is known that a number of simple sugars, for example. 3-amino-3-deoxy-d-glucosamine inhibits the phosphorylation of kanamycin by an enzyme isolated from Pseudomonas.