substances of biological origin that are synthesized by microorganisms and that suppress the growth of bacteria and other microbes as well as viruses and cells. Many antibiotics are capable of killing microbes. Sometimes antibacterial substances extracted from plant and animal tissues are also included among the antibiotics. Every antibiotic is characterized by specific selective action against only certain species of microbes. Hence a distinction is made between broad- and narrow-spectrum antibiotics. The former suppress a variety of microbes (for example, tetracycline acts against bacteria stained by Gram’s method [gram-positive] and against bacteria that are not stained [gram-negative] as well as against rickettsiae); the latter suppress only the microbes of a particular group (for example, erythromycin and oleandomycin suppress only gram-positive bacteria). Because of the selective nature of their action, some antibiotics can inhibit the life processes of pathogenic microorganisms at concentrations that do not injure the host cells. They are therefore used in the treatment of various infectious diseases of man, animals, and plants. The microorganisms that form antibiotics are antagonists of the microbial competitors surrounding them. The latter belong to other species, and their growth is inhibited by the antibiotics. Credit for the idea of using the phenomenon of microbial antagonism to suppress pathogenic bacteria is due I. I. Mechnikov, who proposed the use of lactobacilli present in sour milk to suppress injurious putrefactive bacteria found in the human intestine.

Until the 1940’s antibiotics possessing therapeutic activity were not isolated in pure form from cultures of microorganisms. The first such antibiotic was tyrothricin, obtained by the American scientist R. Dubos (1939) from a culture of the spore-forming aerobic bacillus Bacillus brevis. The potent therapeutic activity of tyrothricin was established in experiments on mice infected with pneumococci. In 1940 the English scientists H. Florey and E. Chain, working with penicillin formed by the fungus Penicillium notatum (discovered by the English bacteriologist A. Fleming in 1929), were the first to isolate penicillin in pure form and observe its remarkable therapeutic properties. In 1942 the Soviet scientists G. F. Gauze and M. G. Brazhnikova obtained gramicidin S from a culture of soil bacteria, and in 1944 the American scientist S. Waksman obtained streptomycin from the actinomycete Streptomyces griseus. About 2,000 different antibiotics from cultures of microorganisms have been described, but only a few of them (about 40) can be used as drugs because the others, for various reasons, do not have chemotherapeutic action. Antibiotics can be classified according to their origin (from fungi, bacteria, actinomycetes, and so on), chemical nature, or mechanism of action.

Antibiotics from fungi. The most important antibiotics from fungi are those of the penicillin group formed by many strains of Penicillium notatum, P. chrysogenum, and other species of mold fungi. Penicillin inhibits the growth of staphylococci in a dilution of 1 to 80 million and has low toxicity for humans and animals. It is destroyed by the enzyme penicillinase, which is formed by certain bacteria. Scientists obtained from the penicillin molecule its ring moiety (6-aminopenicillanic acid) and then added various radicals to it chemically, thereby creating new polysynthetic penicillins (methicillin, ampicil-lin and so on), which are not destroyed by penicillinase and which suppress some bacterial strains resistant to natural penicillin. Another antibiotic, cephalosporin C, is formed by the fungus Cephalosporium. Its chemical structure is similar to that of penicillin, but it has a broader spectrum of action and inhibits the activity of both gram-positive and some gram-negative bacteria. Semisynthetic derivatives (for example, cephaloridin) obtained from the “ring” of the cephalosporin molecule (7-aminocephalosporinic acid) found application in medical practice. The antibiotic griseofulvin was isolated from cultures of Pencillium griseofulvum and other molds. It inhibits the growth of pathogenic fungi and is widely used in medicine.

Antibiotics from actinomycetes. Antibiotics from actinomycetes are highly varied in chemical nature, mechanism of action, and therapeutic properties. As early as 1939 the Soviet microbiologists N. A. Krasil’nikov and A. I. Koreniako described the antibiotic mycetin, formed by one of the actinomycetes . The first antibiotic obtained from actinomycetes to be used in medicine was streptomycin, which suppresses not only gram-positive bacteria and gram-negative bacilli of tularemia, plague, dysentery, and typhoid but also tubercle rods. The streptomycin molecule consists of streptidine (di-guanidine derivative of mesoinosite), which is united by a glucoside bond to streptobiosamine (a disaccharide containing streptose and methylglucosamine). Streptomycin belongs to the antibiotic group of water-soluble organic bases that includes aminoglucosides (neomycin, monomycin, kanamy-cin, and gentamicin), which have a broad spectrum of action. Antibiotics of the tetracycline group—for example, chlorte-tracycline (also called Aureomycin, biomycin) and oxyte-tracycline (also Terramycin)—are widely used in medicine. They are broad-spectrum drugs, and in addition to bacteria they suppress rickettsiae as well (for example, the causative agent of typhus). By acting on cultures of actinomycetes—the producers of these antibiotics —with ionizing radiation or with one of many chemical agents, scientists were able to obtain mutants that synthesize antibiotics with altered molecular structure (for example, dimethylchlor-tetracycline). Chloramphenicol (also called levomycetin), a broad-spectrum antibiotic, has been produced in recent years—unlike others—by chemical synthesis rather than by biosynthesis. Another such antibiotic is the tuberculostatic agent cycloserine, which can also be obtained by industrial synthesis. The other antibiotics are produced by biosynthesis. Some of them (for example, tetracycline, penicillin) can be obtained in the laboratory by chemical synthesis. However, this method is so difficult and costly that it cannot compete with biosynthesis. Of considerable interest are the macrolides (erythromycin, oleandomycin), which suppress gram-positive bacteria, and the polyenes (nystatin, amphotericin, levorin), which possess antifungal action. There are antibiotics formed by actinomycetes that suppress some forms of malignant neoplasms and are used in the chemotherapy of cancer—for example, actinomycin (also called chrysomallin, aurantin), olivomycin, bruneo-mitsin and rubomitsin S. The anthelmintic hygromycin B is also of interest.

Antibiotics from bacteria. Antibiotics from bacteria are chemically more homogeneous, and most of them are polypeptides. Tyrothricin and gramicidin S (from Bacillus brevis), bacitracin (from B. subtilis), and polymyxin (from B. polymyxa) are used in medicine. Nisin, formed by streptococci, is not used in medicine, but it is used in the food industry as an antiseptic—for example, in preparing canned food.

Antibiotics from animal tissues. The best-known antibiotics from animal tissues are lysozyme—discovered by the English scientist A. Fleming (1922)—an enzyme, a polypeptide of complex structure present in tears, saliva, nasal mucus, spleen, lungs, albumen, and so on, which inhibits the growth of saprophytic bacteria but acts weakly against pathogenic microbes; and interferon, also a peptide, which plays an important role in protecting the body against viral infections. The amount produced in the body can be increased by means of special substances called interferonogens.

Antibiotics can be classified not only by origin but also by the chemical structure of their molecules. Such a classification was proposed by the Soviet scientists M. M. Shemiakin and A. S. Khokhlov: antibiotics of acyclic structure (the polyenes nystatin and levorin); antibiotics of alicy-clic structure; antibiotics of aromatic structure; quinones; oxygen-containing heterocyclic compounds (griseofulvin); macrolides (erythromycin, oleandomycin); nitrogen-containing heterocyclic compounds (penicillin); polypeptides of proteins; and depsipeptides (see Table 1).

A third possible classification is based on differences in the molecular mechanisms of action. For example, penicillin and cephalosporin selectively suppress the formation of the cell wall in bacteria. Several antibiotics selectively inhibit various stages of protein biosynthesis in the bacterial cell. Tetracyclines disturb the fixation of transport ribonucleic acid (RNA) to bacterial ribosomes. The macrolide erythromycin, like lincomycin, blocks the movement of ribosomes along the strand of information RNA. Chloramphenicol impairs ribosomal function at the level of the enzyme peptidyl translocase. Streptomycin and the aminoglucoside antibiotics (neomycin, kanamycin, monomycin, and gen-tamicin) distort the “reading” of the genetic code in bacterial ribosomes. Another group of antibiotics selectively impairs the biosynthesis of nucleic acids in cells at different stages. Actinomycin and olivomycin unite with the matrix of desoxy-ribonucleic acid (DNA) to block the synthesis of information RNA. Bruneomitsin and mitomycin react with DNA like alkylating compounds, and rubomitsin S does so by intercalation. Finally, some antibiotics selectively interfere with the bioenergetic processes. Gramicidin S, for example, blocks oxidative phosphorylation.

Resistance of microorganisms to antibiotics. The resistance of microorganisms to antibiotics is a major consideration in making the correct choice of a preparation for therapeutic purposes . During the first few years after the discovery of penicillin about 99 percent of the pathogenic staphylococci were sensitive to this antibiotic; by the 1960’s no more than 20 to 30 percent remained sensitive. The increase in resistant forms is due to the fact that mutants that are virulent and that become widespread, especially where sensitive forms are suppressed by antibiotics, regularly appear in the bacterial populations. From the population genetics standpoint, this is a reversible process. Because of this, when a particular antibiotic is temporarily removed from the arsenal of drugs, resistant forms of the microbes are again replaced by sensitive forms which reproduce at a faster rate.

Industrial production of antibiotics. Antibiotics are produced industrially in fermenting vats, where microorganisms that produce antibiotics are cultured under sterile conditions on special nutrient media. The breeding of active strains, for which various mutagens are used beforehand to induce active forms, is of considerable importance in this connection. If the original strain of the penicillin producer with which Fleming worked formed penicillin at a concentration of 10 international units per milliliter (IU/ml), then modern producers do so at a concentration of 16,000 IU/ml. These figures reflect the progress of technology. Antibiotics synthesized by microorganisms are extracted and chemically purified. The activity of antibiotics is quantitatively determined by microbiological (according to the degree of antimicrobial action) and physicochemical methods.

Antibiotics are widely used in medicine, agriculture, and various branches of the food and microbiological industries.

Use of antibiotics in medicine. About 40 antibiotics that are not harmful to the human organism are in clinical use. To achieve a therapeutic effect, it is necessary to maintain so-called therapeutic concentrations in the body, especially at the infection site. An increased concentration of the antibiotic may be more potent, but it is likely to be complicated by side effects. If the action of an antibiotic must be intensified, more than one may be used (for example, streptomycin with penicillin), or an antibiotic may be used with other medication (for example, for pulmonary inflammation, ephecillin may be used with hormonal preparations, anti-coagulants, and so on). Combinations of certain antibiotics are toxic and cannot be used together. Penicillins are used for sepsis, pulmonary inflammation, gonorrhea, syphilis, and so on. Ben-zylpenicillin and ekmonovotsillin (a procaine salt of penicillin with ekmolin) are effective against staphylococci. Bicil-lins -1,-3, and -5 (a dibenzylethylenediamine salt of penicillin) are used to prevent rheumatic attacks. A number of antibiotics, such as streptomycin sulfate, paskomitsin, dihydro-streptomycinpantothenate, streptomycin-saluzide, cycloserine, viomycin (florimycin), kanamycin, and rifamycin, are prescribed for the treatment of tuberculosis. Preparations of the synthomycin series are used in the treatment of tularemia and plague; the tetracyclines are used to treat cholera. Lysozyme with ekmolin is used to control the carrier state of pathogenic staphylococci. Broad-spectrum polysynthetic penicillins, for example, ampicillin and geta-cillin, inhibit the growth of the intestinal, typhoid, and dysentery bacilli.

The prolonged and widespread use of antibiotics resulted in the appearance of a great many pathogenic microorganisms resistant to them. A matter of practical importance is the simultaneous development of resistant microbes—the phenomenon of drug cross resistance. To prevent the formation

of resistant forms, the widely used antibiotics are replaced from time to time and they are never applied locally to wound surfaces. The diseases caused by antibiotic-resistant staphylococci are treated with polysynthetic penicillins (methicillin, oxacillin, cloxacillin, and dicloxacil-lin), erythromycin, oleandomycin, novobiocin, lincomycin, leucomycin, kanamycin, and rifamycin. Shincomitsin and iozamitsin are used against staphylococci resistant to many antibiotics. Besides resistant forms, antibiotics (especially streptomycin) can also give rise to the so-called dependent forms (microorganisms that grow only in the presence of antibiotics). If unwisely used, antibiotics activate pathogenic fungi present in the body, causing candidiasis. Nistatin and levorin are prescribed to prevent and treat this disease.

Side effects sometimes result from antibiotic therapy. The prolonged administration of large doses of penicillin has a toxic effect on the central nervous system, streptomycin affects the acoustic nerve, and so on. These phenomena are treated by reducing the dose. Sensitization may be manifested regardless of the dose or method of administration, and it may result in exacerbation of an infection (entry of large amounts of toxins into the blood owing to mass death of the causative agent), in recurrences of diseases (because of suppression of the body’s immunobiological reactions), in superinfection, and in allergic reactions.

The availability of new antibiotic salts made it possible to overcome the specific toxicity of some antibiotics. For example, pantomycin, the pantothenic salt of streptomycin, is indistinguishable from streptomycin in therapeutic effect and produces a good response in patients who cannot tolerate streptomycin. The ascorbic acid salt of dihydro-streptomycin also proved to be much less toxic than streptomycin. If an allergy to penicillin develops, cephalosporin is used.

During treatment with antibiotics, it is essential to simultaneously introduce vitamins. The diet should be rich in proteins, since streptomycin lowers the quantity of pantothenic acid (vitamin B₃) in the organism, phthavazid and cycloserine act on vitamin B₆, and a protein shortage lessens the results of the treatment.

Use of antibiotics in livestock raising. Antibiotics are used to treat erysipelas and dysentery of swine, anthrax, and strangles of horses, pullorum disease of poultry, actinomycosis, bronchial pneumonia, gastrointestinal diseases of young animals, sepsis, metritis, vaginitis, and many other diseases. Antibiotics are also widely used with feed to stimulate the growth and development of farm animals. Both pure and so-called fodder preparations—the unpurified products of the fermentation of various actinomycetes, bacteria, and molds—are ordinarily utilized for this purpose. In addition to antibiotics, the preparations contain vitamins, amino acids, and other products of microbiological synthesis. They have an overall beneficial effect on growth, metabolism, fecundity, and resistance to unfavorable factors and infectious diseases. The use of antibiotics (mainly in small doses) in the feed of young animals (mostly swine and poultry) reduces the time required for fattening and increases the weight gain, and in hens, the egg yield.

Use of antibiotics in horticulture. Antibiotics penetrate into plants through the roots and leaves and then spread to the tissues, greatly increasing resistance to fungus and bacterial diseases. At certain concentrations, antibiotics can increase the germinating capacity of seeds, accelerate plant development, and stimulate root formation. Methods of using antibiotics include the treatment of seeds, spraying of plants, and injection into tree trunks. Streptomycin and terramycin are used against such diseases as bacterial blight of apples, pears, and cherries, bacterial wildfire of tobacco, and blackleg of potatoes. Griseofulvin and others are used to treat fungus diseases.