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PHRM 304
The tetracyclines were the first major group of antimicrobial agents for which the term broad spectrum was used- namely, they exhibit activity against both gram-positive and gram-negative bacteria. Although they bind both the eukaryotic 80S, and the bacterial 70S units of Ribosome, the latter is more sensitive, making tetracyclines effective and selective antimicrobial agents. Contraindicated to young and pregnant as it form chelate with calcium and thus causes problem in development of bones.
Tetracyclines enter through porins in Gram-negative bacteria, and through their lipophilicity in Grampositive bacteria. They pass through the cytoplasmic membrane via active transport, where they are mistaken for food. Available agents:
Tetracycline
Minocycline
Doxycycline
Antibacterial synthesis:
agents
which
impair
protein
Inhibition of protein synthesis by an effect on ribosome: Drugs acting on 30S subunits: - Aminoglycoside - Tetracyclines Drugs acting on 50S subunit: - Chloramphericol - Erythromycin
Ribosomes are complexes of RNA and protein that are found in all cells. The ribosome functions in the expression of the genetic code from nucleic acid into protein, in a process called translation. Ribosomes do this by catalyzing the assembly of individual amino acids into polypeptide chains; this involves binding a messenger RNA (mRNA) and then using this as a template to join together the correct sequence of amino acids. The ribosomal subunits of prokaryotes and eukaryotes are quite similar. The unit of measurement is the Svedberg unit, a measure of the rate of sedimentation in centrifugation rather than size and accounts for why fragment names do not add up.
Prokaryotes (are a group of organisms that lack a cell nucleus) have 70S ribosomes, each consisting of a small (30S) and a large (50S) subunit. Eukaryotes have 80S ribosomes, each consisting of a small (40S) and large (60S) subunit.
Tetracycline
Tetracyclines are named for their four (tetra-) hydrocarbon rings (-cycl-) derivation (-ine).
Drugs enter bacteria in part by passive diffusion, in part by an energy-dependent process of active transport, result in susceptible cells concentrate the drug, the intracellular drug concentration is much higher than the extracelluar one. Once inside the cell, tetracyclines bind reversibly to receptors on the 30S subunit of the bacterial ribosome in a position that blocks the binding of the aminoacyl-tRNA to the accepter site on the mRNAribosome complex.
Antibacterial activities
The tetracyclines as a whole have a broad spectrum of activity and are the most widely prescribed after penicillins. Bacteriostatic for many gram-positive and gramnegative bacteria. Bacteriostatic for chlamydiae, spirochetes amoebae). mycoplasma, rectettsia, & some protozoa (e.g.
Structure: Tetracycline
The tetracyclines form stable chelate complexes with many metals, e.g., Ca++, Mg++, Fe++, etc. Chelation is an important feature of the chemical and clinical properties tetracyclines. The acidic functions of the tetracyclines are capable of forming salts through forming chelation with metal ions. Deposition of tetracyclines in the bone and teeth occurs during calcification in growing children, which causes discoloration and hypoplasia of the teeth.
Tetracyclines attack protein synthesis in mammalian cells as well as in bacterial cells. Fortunately, bacterial cells accumulate the drug far more efficiently than mammalian cells and are therefore more susceptible. Unfortunately, it does have side-effects due to the fact that it kills the intestinal flora (such as Escherichia coli) that make vitamin K (mainly vitamin K2)- a vitamin which is needed as part of the clotting process. Thus tetracyclines delay blood coagulation process.
Structure: Tetracycline
SAR of tetracyclines
A. Linear arrangement of four rings is essential for activity. Derivatives having fewer than 4 rings are inactive. B. Opening of rings or addition of ring produces inactive compounds. Tetracyclines contain four fused rings (A-D), one of which, D, is aromatic; rings A and B contain sites of unsaturation. Essentially all alterations to the general tetracycline ring skeleton are deleterious; breaking any ring, disrupting aromaticity in ring D, or aromatization of ring A or C destroys all tetracycline activity.
SAR of tetracyclines
C. The presence of 4-dimethylamino is essential for activity and for optimum distribution. Removal of the 4-dimethylamino group affords a loss of about 75% of the antibiotic effect of the parent tetracyclines. Removal of the dimethylamino group at C4 diminishes in vitro activity and abolishes in vivo activity.
D. Modifications to the functional groups on ring A and the bottoms of rings B, C, and D are generally not tolerated, but extensive modification is possible elsewhere. From C-5 to C-9 can be altered in various ways: a. Removal of 5-OH (present in oxytetracycline) to give 5-deoxycompounds does not change the activity. b. Neither 6-methyl nor 6-hydroxy is essential. Neither the hydroxyl nor the methyl at C6 is essential for activity; no direct ribosome interaction is observed for the C6 substituents. c. Electron withdrawing groups (-Cl, -NO2, protonated dimethyl amino group) at 7 enhance the activity.
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E. The conjugation between C-10 and C-12 is essential for activity. F. In the 2-amide moiety, one amide hydrogen can be replaced without loss of activity.
Tetracyclines were the first broad-spectrum antibiotics and have been used successfully for decades to treat both gram-positive and gram negative bacterial infections. Chlortetracycline was the first tetracycline to be isolated, in 1948, from Streptomyces aureofaciens. Biochemical probing identified multiple tetracycline binding sites within 30S, one of which resides in the decoding A-site and seems to be responsible for the antibiotic effect of tetracycline. It has been accepted for some time that tetracycline interferes with proper tRNA binding to the A-site.