The penicillin

The penicillin

The first of the modern antibiotics and still one of the most useful, penicillin is produced by penicillium notated. Penicillium Chrysogenum, and by other species of molds. As previously noted, the first of these was isolated by Fleming in 1929, when he found it as a contaminant on a culture plate. Florey and his associates at Oxford University isolated the active ingredient and used the crude material clinically in 1940. Penicillin is selective for gram-positive bacteria, some spirochetes, and the gram-negative diplococci (Neisseria). Although it is rarely toxic in human patients, it may give rise to sensitivity reactions which vary from a mild skin reaction to severe anaphylaxis.

Penicillins are a class of -lactam antibiotics of the related structure with slightly different properties and activities. All penicillins have a common basic nucleus, a fused -lactam-thiazolidine ring with different side chains which give each its unique properties. Several chemically different penicillins are produced by biosynthesis in a single fermentation.

Natural penicillins can be prepared as salts of sodium, potassium, procaine, and other bases. The crystalline sodium or potassium salts are freely soluble in water, ethyl alcohol, ether, esters, and dioxane but only slightly soluble in chloroform and benzene. In pure crystalline form penicillins are colorless. The natural penicillins are inactivated by heat, cysteine, sodium hydroxide, penicillinase, and hydrochloric acid. They are not affected by the action of saliva or bile. Penicillin V exhibits greater stability than others in acids. Some of the new semisynthetic penicillins may be much more stable than those produced by biosynthesis, the “natural penicillins”.

The first break in the production of the new semisynthetic penicillins was the discovery that the basic nucleus of the molecules, common to all penicillins, is 6-aminopenicillanic acid. The next step was to obtain 6-aminppenicillanic acid in quantity so that suitable side chains could be attached to it. This was a very difficult task, but it was then discovered that under suitable conditions P. Chrysogenum would produce the basic nucleus in abundance by “interrupted” biosynthesis, by amidase enzymes, leaving the 6-aminopenicillanic acid free for attaching new side chains as desired.

One of the first semisynthetic penicillins to be produced for clinical use was phenethicillin. It is more readily absorbed than penicillin V and just as effective as penicillin G. Another of the semisynthetic penicillins, methicillin, is more resistant to penicillinase and therefore is less likely to be inactivated.

Ampicillin

Ampicillin, another semisynthetic penicillin, acts against a broad spectrum of bacteria. It is strongly bactericidal and lacks toxicity, but it is not resistant to penicillinases. It is relatively stable to gastric acid and hence can be administered orally. The chemical structure of these three penicillins. Several additional semisynthetic penicillins have been developed for chemotherapeutic use.

Penicillins interfere with the final stages of peptidoglycan biosynthesis. The penicillins inhibit the transpeptidase reaction, namely, the cross-linking of the two linear polymers. The penicillins are bacterial to growing cells.

Cephalosporins

Cephalosporins are a group of antibiotics produced by a species of marine fungus, Cephalosporium acremonium, which bears considerable resemblance to penicillium spp. They are effective against Gram-positive and Gram-negative bacteria. The cephalosporins have antibacterial properties similar to those of the semisynthetic penicillins. They are effective therapeutically and have a low toxicity. The nucleus off the cephalosporins resembles that of penicillin. As with penicillin, several semisynthetic cephalosporins have been manufactured commercially for therapeutic use.

As would be anticipated from the similarity in chemical structure of penicillin and cephalosporins, the mode of action of the cephalosporins is that of inhibition of the cross-linking transpeptidase. They are bactericidal to growing cells.

Cycloserine

Cycloserine, a relatively simple compound, is related in structure to alanine. It was originally discovered as an antibiotic produced by streptomyces and is now manufactured through chemical synthesis. The main use of this antibiotic is in tuberculosis therapy. However, because of potential undesirable side effects, its utilization is limited.

Cycloserine manifests its inhibitory effect on peptidoglycan synthesis by interference with synthesis of the peptide moiety of the peptidoglycan. Specifically, it inhibits both alanine racemase and D-alanine synthetase, the enzymes involved in the synthesis of the pentapeptide side chains.

Bacitracin

Bacitracin is a product of Bacillus subtilis and chemically is a polypeptide. Because of its toxicity to animal and human cells, it cannot be used for systematic chemotherapy. It does have application for topical treatment of infections caused by Gram-positive bacteria.

Bacitracin interferes with regeneration of the monophosphate form of bactoprenol from the pyrophosphate form.

Vancomycin

Vancomycin is an antibiotic produced by Streptomyces oriental. It is a complex chemical entity consisting of amino acids and sugars.

Vancomycin inhibits peptidoglycan synthesis by binding the D-alanine group on the peptide side chain of one of the membrane-bound intermediates.

A schematic summary of the modes of action of some antibiotics that exert their antibacterial effect through interference with cell-wall synthesis.

Damage to cytoplasmic membrane

Several polypeptide antibiotics produced by Bacillus spp. have the ability to damage the cell-membrane structure. They adversely affect the normal permeability characteristics of the cell membrane. Included in this category are the polymyxins, gramicidins, and tyrocidines.

The polymyxins are particularly effective against Gram-negative organisms, while the Tyrocodines and gramicidins are more effective Gram-positive organisms.

These agents are bactericidal; they cause a leakage from the cytoplasmic content of the cell. Because of their toxicity to tissue, they have limited application in chemotherapy. Another category referred to as polyene antibiotics are large ring structures with many double bonds. Examples are nystatin, produced by Streptomyces Noursei, and amphotericin, produced by Streptomyces Nodosus. Polyene antibiotics act upon cells which have sterols in their cytoplasmic membrane. They act upon fungi (including yeasts) and animal cells do not affect bacteria. Their antimicrobial action is attributed to their ability to increase cell permeability.

Inhibition of nucleic acid and protein synthesis

The process by which the cell synthesizes nucleic acids and proteins. Synthesis of these substances involves a number of intricate biochemical reactions, it is recommended that these reactions be reviewed to better comprehend the mode of action of those antibiotics that interfere with these metabolic processes.

Examples of the major categories of antibiotics affecting nucleic acid and protein.

Streptomycin

Streptomycin is produced by Streptomyces griseus, a soil organism isolated by Schatz, Bugie, and Waksman, who reported on its antibiotics activities in 1994. It is particularly important because it inhibits many organisms resistant to sulfonamides and penicillin. Its antibacterial spectrum includes many Gram-negative bacteria, including Francisella tularensis and some organisms in the salmonella group. It is inhibitory for several species of Mycobacterium, including Mycobacterium tuberculosis. Highly purified streptomycin is nontoxic to humans and other animals when given in small doses, but it appears to have a cumulative detrimental effect on a specific region of the nervous system when gives as a medication over long periods of time.

Streptomycin is characterized chemically as an, aminoglycoside antibiotic; its structure. Other aminoglycoside antibiotics are kanamycin, produced by Streptomyces Kanamyceticus, and neomycin, produced by Streptomyces fragile and other species of Streptomyces.

Streptomycin and other aminoglycoside antibiotics inhibit protein synthesis by combining irreversibly with the 30S subunit mRNA. Thus the normal synthetic sequence is disrupted.

References

Arvind, Keshari K. and Kamal K Adhikari. A Textbook of Biology. Vidyarthi Pustak Bhander.

Michael J.Pleczar JR, Chan E.C.S. and Noel R. Krieg. Microbiology. Tata Mc GrawHill, 1993.

Powar. and Daginawala. General Microbiology.

Rangaswami and Bagyaraj D.J. Agricultural Microbiology.