We are going to explain you everything about antibiotics. Antibiotics are produced by microorganisms chemicals that can inhibit bacteria and other microbes growth and cause death. Antimicrobial action of antibiotics is selective: at some organisms, they are stronger, at the other – weaker or provide no effect. And selectively they have an effect on antibiotics and animal cells so that they differ in degree of toxicity and effect on blood and other biological fluids. Some antibiotics are of considerable interest to chemotherapy and can be used to treat a variety of microbial infections in humans and animals.

Historical Background

In traditional medicine, for wounds and tuberculosis treatment it has been long used lichens extracts. Later in the ointment for superficial wounds treatment, people began to include extracts of Pseudomonas aeruginosa bacteria, though no one knew how they helped, and antibiosis phenomenon was unknown.

However, some of the first scientists – microbiologists were able to discover and describe antibiosis (inhibition of organisms’s growth among others). The fact that antagonistic relationship between different microorganisms is shown in their growth in mixed culture. Prior to the development of pure culture techniques, different bacteria and mold were grown together, ie, in optimal conditions for antibiosis manifestation. Louis Pasteur in 1877 even described antibiosis between soil bacteria and pathogenic bacteria – anthrax. He even suggested that antibiosis may become basic therapy.

The first antibiotics were allocated even before they became known for their ability to inhibit microorganisms’ growth. Thus, in 1860 it was obtained in crystalline form blue pigment known as pyocyanin released by small rod-shaped bacteria of strain – Pseudomonas, but its antibiotic properties were discovered only after many years. In 1896 from mold cultures it was successfully crystallized such chemical, known as mycophenolic acid.

Gradually it became clear that antibiosis has chemical nature and is caused by specific chemical compounds production. In 1929, Alexander Fleming, monitoring antagonism between Penicillium notatum and staphylococcus in mixed culture, discovered penicillin and suggested its use possibility for medicinal purposes. The antagonistic relationship between pathogenic microbes for plants and non-pathogenic micro-organisms of soil identified in mixed cultures, pathologists are interested in, and they tried to use this phenomenon for the control of plant diseases. It is known that there is a certain soil fungus which reduces damping off germs; in 1936 from fungus culture, antibiotic was isolated, dubbed gliotoxin. This discovery confirmed the importance of antibiotics as means of disease prevention.antibiotics
Among the first researchers to take a targeted search for antibiotics was René Dubos. Experiments conducted by him and his staff led to the discovery of antibiotics produced by certain soil bacteria, their isolation in pure form and use in clinical practice. In 1939 Dubos got tyrothricin – a complex of antibiotics consisting of gramicidin and tyrocidine. It was the impetus for other scientists who have discovered even more important for clinic antibiotics. In 1942 Howard Florey with colleagues at Oxford University re-examined penicillin proving the possibility of its clinical use as a non-toxic treatment for many acute infections. At the same time, these substances were called antibiotics.

Selman Waksman with his students at Rutgers University, USA, studied actinomycetes (such as Streptomyces), and in 1944 discovered streptomycin, an effective means of tuberculosis and other diseases treatment. After 1940 it has been received many clinically important antibiotics, including bacitracin, chloramphenicol, chlortetracycline, oxytetracycline, amphotericin B, cycloserine, erythromycin, griseofulvin, kanamycin, neomycin, nystatin, polymyxin, vancomycin, viomycin, cephalosporins, ampicillin, carbenicillin, aminoglycosides, streptomycin, gentamycin. Currently, more and more antibiotics were open. In the mid-1980s in the US antibiotics were prescribed more often than any other medication, except sedatives and tranquilizers.

Antibiotics Production

Antibiotics ProductionThe ability to produce antibiotics not all microorganisms possess, but only some strains of certain species. Thus, they are some strains of penicillin form and Penicillium notatum P. chrysogenum, streptomycin and – a certain strain of Streptomyces griseus, while the other strains of the same species did not produce any antibiotics, or produce, but other. There are also differences between strains of antibiotics, and these differences may be quantitative or qualitative. One strain, for example, gives the maximum yield of antibiotic when culture grows on the medium surface and is in a steady state, and the other – only when it is immersed in the medium culture and continuously shaken.

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Some microorganisms produce not only one, but several antibiotics at one and the same time. So, Pseudomonas aeruginosa produces pyocyanase, pyocyanin, poli – lipoic acid and other pio-compounds; Bacillus brevis produces gramicidin and tyrocidine; P. notatum – penicillin and pentyne; Aspergillus flavus – penicillin and aspergillic acid; Aspergillus fumigatus – fumigacin, fumigacin and gliotoxin; Streptomyces griseus – streptomycin, mannosylstreptomycin, cycloheximide and stereocilin; Streptomyces rimosus – oxytetracycline; Streptomyces aureofaciens – chlortetracycline and tetracycline.

The same antibiotic can be produced by microorganisms of various kinds. Thus gliotoxin from Gliocladium and Trichoderma species, and Aspergillus fumigatus, and others. Different microorganisms or strains may produce different chemical forms of the same antibiotic, such as penicillin or various different streptomycin forms.

In recent years it has been isolated and described a huge number of antibiotics produced by various organisms. The ability to produce antibiotics possesses a spore-forming and non-spore-forming bacteria, and in addition, more than half is studied on the subject of fungal genera.

Non-spore bacteria. This group of bacteria, previously called Bacillus pyocyaneus, and later known as Pseudomonas aeruginosa, is highlighted pyocyanin and pyocyanase. Other non-spore forming bacteria also produce antibiotics, very different in chemical structure and antibacterial properties. An example is a colicin produced by various strains of E. coli (Escherichia coli).

Spore-forming bacteria. Many species of spore-forming bacteria produce various antibiotics. Thus, Bacillus subtilis strains produce bacitracin, subtilin, etc.; B. brevis – tyrothricin, B. polimixa (B. aerosporus) – polymyxin (aerosporin). B. mycoides, B. mesentericus and B. simplex variety allocate yet poorly understood compounds: Batsillin, colistin etc. Many of these inhibit fungi growth.

Actinomycetes. Except for penicillin, the most important antibiotics are used as chemotherapeutic agents, obtained from actinomycetes. Currently, 200 of such compounds were produced or described in more thereof. Some of them are widely used in infectious diseases treatment on humans and animals. Such antibiotics include streptomycin, tetracycline, erythromycin, novobiocin, neomycin, etc. Some of them have basically antibacterial action, others – antifungal and third group is major active against certain viruses.

Fungi. Fungi in medicine are referred to microorganisms belonging to fungi culture. This is one of the most important antibiotics’ producers. They produce cephalosporin, griseofulvin, mycophenolic acid, penicillin acid gliotoxin, colistin, aspergillic acid and many other compounds.

Other organisms. Seaweed. Many algae are capable of producing substances having antibiotic properties, but so far none of them have found a clinical application.

Lichens. Antibiotics, produced by lichens are lichenin and usnic acid.

Higher plants. Higher green plants also produce antibacterial substances similar in its properties to true antibiotics. These are volatile – allicin, tomatine, and others.

Animals. Among animal products with antibacterial properties, lysozyme is occupied an important place. Many protozoans, maggots, and a few other animals can digest live bacteria and fungi, however, it is not clear to what extent this ability is related to the generation of substances with antibiotic properties.

Chemical Nature

Antibiotics classification several systems were developed, and have been based upon various criteria: origin, antimicrobial properties, toxicity to animals, solubility or chemical nature. The most logical final approach to classification seems. Antibiotics can, for example, divide into lipids, pigments, polypeptides, sulfur-containing compounds, quinones, ketones, lactones, glycosides, and nucleosides.

Some antibiotics are able to synthesize (pyocyanin, cycloserine and, most importantly, penicillin). However, all of penicillin G (benzylpenicillin), used in medicine until 1962, had a biological origin. The combination of biological and chemical synthesis has created a large family of new penicillins, many of which find application as pharmaceuticals.

Mechanism of Action

Antibiotics are generally considered to be bacteriostatic agents, i.e. inhibitors of growth, although some of them have a pronounced bactericidal or bacteriolytic action. Many antibiotics, such as actinomycin, are highly toxic with respect to animal tissues and used only as antitumor agents; others, particularly penicillins or completely non-toxic (such as streptomycin) have only a low level of toxicity. Broad-spectrum antibiotics (e.g., tetracycline) disrupt normal intestinal microbial flora, and can cause gastrointestinal disturbances or promote secondary infections.

Some (such as tyrothricin) have hemolytic activity, i.e. destroy red blood cells; others (e.g., imipimen), in contrast, inactivate body cells. As antibiotics inherent selective antibacterial activity, none of them can be used as a general disinfectant against all bacteria.

Penicillin and erythromycin are active mainly against cocci forms and a variety of Gram-positive bacteria, and streptomycin – against tubercle bacillus. Penicillin and streptomycin relatively have little effect on fungal flora and viruses, although the first has some activity against major viruses, such as anti-virus psittacosis, and the second – against some pathogens Rickettsia and tropical granuloma inguinale. However, a number of antibiotics, especially tetracycline, perform on many gram-positive and gram-negative bacteria as well as viruses, rickettsiae, and large viruses. Some antibiotics have high antifungal activity, while others – antitumor effect.

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The site of Action. Antibiotics are different from each other not only in their chemical structure but also on actions of application site in the microbial cell. Effect of antibiotics used in low concentrations generally is directed to specific features of pathogenic microorganisms. Bacteria and molds cell walls are very different from the cell membrane of animal cells, and many non-toxic antibiotics namely block cell walls formation.

Since there are penicillin, bacitracin, cephalosporins, cycloserine used in the clinic in bacterial infections treatment, and also griseofulvin, which is used for skin fungal diseases. A particularly important role in bacterial cell activity plays its plasma membrane, located at cell wall. It regulates cell passage of nutrients and waste products output, there occur many enzymatic processes.

Polymyxin antibiotic is bound to the cell membrane of Gram-negative bacteria and may interfere with its function. Tyrocidine has chemical properties of detergent and destroys membrane. Streptomycin has an influence on them: newly synthesized membrane is defective, and cell loses vital ingredients for yourself. Nystatin, contacting cell membranes of various yeasts and molds, leads to essential element loss in cells – potassium. In all living cells, protein synthesis occurs.

Chloramphenicol specifically blocks this process in many bacteria. Tetracyclines inhibit protein synthesis, as well, but no less important side effect is complexed formation with metals influencing on binding to calcium, magnesium, and manganese in a cell. Erythromycin also affects protein synthesis. Mechanisms of action study of different antibiotics have given a lot of useful information about biochemical processes occurring in microorganisms cells. Even those antibiotics that are not used for therapeutic purposes, can be used as an important means of biochemical research.

The main mechanism by which penicillin kills bacteria (including cultured, that is used to determine the sensitivity of bacteria to antibiotics) is now well understood. Penicillin performs on the cell wall of bacteria; it is an essential component of peptidoglycan – complex structures, where like sugar glucose linked together by peptide cross-bridges formed by amino acids. Normally wall peptidoglycan of bacteria attached to mechanical strength and stability.

Penicillin changes their biosynthesis, that is losing required strength. As a result, contents of bacterial cell disappear and the cell dies. Since mammalian cells are completely different, not containing peptidoglycan, penicillin is almost no effect on them. Thus, penicillin usually is harmless to human, except for rare side effects, such as severe allergic reactions.

Resistance to antibiotics. Many bacteria upon prolonged contact with antibiotics are able to adapt to their action; it leads to the emergence of resistant bacteria strains. Thus, Staphylococcus aureus culture, originally penicillin-sensitive, may become resistant to it. Other strains of S. aureus produce enzyme penicillinase, which breaks penicillin, and therefore is capable of causing severe infections, even in those receiving antibiotic.

Tubercle bacillus, Mycobacterium tuberculosis, as initially sensitive to streptomycin, in some cases, adapt to it. Some strains of microorganisms acquire resistance to multiple antibiotics. In recent years, many doctors have expressed fears that widespread fascination with antibiotics drastically reduces their effectiveness in the treatment of gonorrhea, typhoid fever, pneumococcal pneumonia, tuberculosis, meningitis and other serious illnesses.

Clinical ApplicationsClinical Applications

Antibiotics have revolutionized in medical practice. Among many antibiotics widely used as chemotherapeutic agents in the largest quantities penicillins, cephalosporins, streptomycin, and other aminoglycosides, chloramphenicol, tetracyclines, and erythromycin are applied. In addition, important antibiotics are bacitracin, polymyxin, neomycin, nystatin, and griseofulvin. In certain cases, other antibiotics are also used.

Penicillin is commonly used to treat staph infections – osteomyelitis, infectious arthritis, pneumonia, bronchitis, empyema, endocarditis, boils, laryngotracheitis, mastitis, meningitis, otitis media, peritonitis, infected wounds and burns, septicemia, sinusitis, tonsillitis and many other diseases.

It is successfully used for different infections treatment caused by anaerobic and hemolytic streptococci, pneumococci, gonococci, meningococci, anaerobic clostridia (gas gangrene pathogens), diphtheria bacillus, anthrax, spirochetes, and many other bacteria. However, in mixed infections caused by gram-negative bacteria, as well as malaria, tuberculosis, viral infections, fungal and other diseases penicillin is ineffective. The toxic effect of penicillin is manifested mainly in the form of allergic reactions (even at the minimum dose) and seizures (when administered in very large doses).

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Cephalosporins’ chemical structure is similar to penicillin, but are highly resistant to degradative enzymes action (beta-lactamases) that are produced by some bacteria for protection against penicillin. Therefore, cephalosporins are highly active with respect to coliform bacteria (gram-negative rod-shaped bacteria such as Escherichia coli), normally inhabiting large intestine, and moderately active against a very dangerous Pseudomonas aeruginosa, which causes severe damage to the skin. Currently, we receive a large number of cephalosporins, more among them – cephalothin, cefazolin, cephalexin, cefamandole, defoksitin, and ceftriaxone are used in clinical practice. These compounds are especially valuable in cases of severe nosocomial infections, when a high probability of infection by resistant strains is possible, as well as in cases of proven pathogen resistance to older and less effective antibiotics.

Streptomycin is used in many infections. This is an effective treatment for meningitis, endocarditis, laryngotracheitis, as well as urinary tract and lung diseases caused by bacillus of Pfeiffer (Hemophilus influenzae). Also, they are amenable to treatment with streptomycin meningitis, pneumonia, and urinary tract infections, if the cause of these diseases is sensitive thereto strains of Escherichia coli, Proteus vulgaris, Klebsiella pneumoniae (Friedlander’s bacillus), Aerobacter aerogenes and Pseudomonas.

It is effective in meningitis caused by susceptible to antibiotic strains of Salmonella, and tularemia. In addition, streptomycin is used in peritonitis, liver abscesses, infections of biliary tract and empyema caused by susceptible to the microorganism, tuberculosis, chronic lung infections and endocarditis caused primarily by Gram-negative bacteria, is resistant to penicillin but sensitive to streptomycin bacteria. At the same time, some toxicity streptomycin has and can determine dizziness, deafness and other undesirable phenomena.

In addition, pathogens quickly become resistant to this antibiotic. Side effects persist largely by reducing dose and less frequent administration of streptomycin and resistance agents (in particular for tuberculosis treatment) – its application together with other substances, such as a p-aminosalicylic acid hydrazide, and isonicotinic acid.

Other aminoglycosides. In addition to streptomycin in a number of other medicine, aminoglycosides are used (gentamicin, tobramycin, kanamycin). As seen from their generic names, they all contain amino sugars linked by a glycosidic bond. Antibiotics in this group such as streptomycin have severe toxicity, especially regarding auditory and vestibular (determining the sense of balance) systems, but often also to the kidney. The action of these antibiotics generally is amenable to aerobic gram-negative flora, while the majority of Gram-positive bacteria exhibits high resistance to them.

Chloramphenicol and tetracyclines. Judging by cross-resistance of various bacteria and spectrum of antimicrobial action of these antibiotics, especially tetracycline, have similar biological properties. They are effective when taken orally and are widely used in many infectious diseases caused by bacteria and some large viruses. Such diseases include typhoid fever, various forms of typhus, spotted fever, gonococcal infections, syphilis, brucellosis, urinary tract infection, lymphogranuloma venereum, and many others. These antibiotics are also effective in most diseases, for penicillin treatment which is shown, and are often prescribed for penicillin-resistant infections and in cases where oral therapy is preferred.

Erythromycin and novobiocin. Erythromycin and other antibiotics (for example, carbomycin, oleandomycin) have special (macrolide) chemical structure and novobiocin is characterized by broad spectrum – they are the same as that of penicillin and some female but Gram-negative bacteria.