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Presently, the name "tetracycline" refers to a number of antibiotics of either natural, or semi-synthetic origin, derived from a system of four linearly annelated six-membered rings (1,4,4a,5,5a,6,11,12a-octahydronaphthacene) with a characteristic arrangement of double bonds. The tetracycline molecule possesses five asymmetric centers: C-4, -4a, -5a, -6, and -12a.

Chemical properties
The reactions that tetracyclines undergo are generally of a sophisticated nature, dictated by the complex functionality and the sensitivity of the molecules to mild reaction conditions (acid, base, heat).

Acidic conditions
When exposed to dilute acid conditions, tetracycline undergoes dehydration to yield anhydrotetracycline. Anhydroterramycin suffers further cleavage and lactonization to apoterramycin:

Diluted acid promotes epimerization at C-4 as well.

Basic conditions
Mild alkali attacks 11a carbon of tetracycline, which is transformed to isotetracycline:

Formation of complexes
Tetracycline possesses a great tendency to form complexes with a number of chemical species, due to its B- and C-ring oxygen atoms:

It complexes most readily with Fe3+, Fe2+, Cu2+, Ni2+, Co2+, Zn2+, Mn2+, Mg2+, Ca2+, Be2+, Al3+ among metal ions, phosphates, citrates, salicylates, p-hydroxybenzoates, saccharin anion, caffiene, urea, thiourea, polivinylpyrrolidone, serum albumin, lipoproteins, globulins, and RNA

Tetracycline is a short-acting antibiotic that inhibits bacterial growth by inhibiting translation. It binds to the 30S ribosomal subunit and prevents the amino-acyl tRNA from binding to the A site of the ribosome. It also binds to some extent to the 50S ribosomal subunit. This binding is reversible in nature. Additionally tetracycline may alter the cytoplasmic membrane of bacteria causing leakage of intracellular contents, such as nucleotides, from the cell.



Absorption: Bioavailability is less than 40% when administered via intramuscular injection, 100% intravenously, and 60-80% orally (fasting adults). Food and/or milk reduce GI absorption of oral preparations of tetracycline by 50% or more.

Protein binding: 20 - 67% protein bound

Route of elimination   They are concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in a biologically active form. Half life is 6-12 hours.

Antimicrobial properties
In the 1950s, when most of the tetracyclines were discovered, their antimicrobial spectrum was broader than of any othen antibiotic then known. Tetracyclines are characterized by their exceptional chemotherapeutic efficacy against a wide range of Gram positive and Gram negative bacteria, richettsia, spirochetes, and large viruses, such as members of the lymphogranuloma group. The main indications for the use of tetracyclines are infections due to Escherichia coli and Haemophilus influenzae, infections of the bile duct, bacterial respiratory disorders including bronchitis prophylaxis, mixed infections arising from the mouth, pharynx, or intestinal tract, brucellosis, tularemia, plague and other pasteurelloses, leptospirosis, lymphogranuloma inguinale, cholera, and rickettsiosis. Because of the development of strains of microorganisms resistant to the tetracyclines, these antibiotics have lost some of their usefulness. They are no longer the drugs of first choice for treatment of staphylococcal, streptococcal, or pneumococcal infections. The individual tetracyclines differ less in their potency that in pharmacokinetic properties such as resorption, tissue diffusion, and elimination.

RESISTANCE:  Two genes have been recognized that contribute to the resistance in tetracyclines tet and otr . They donot allow the binding of tetracycline with the aminoacyl t RNA by changing the adenine to guanine.

1. Tetracycline molecules comprise a linear fused tetracyclic nucleus (rings designated A, B, C, and D to which a variety of functional groups are attached. The simplest tetracycline to display detectable antibacterial activity is 6-deoxy-6-demethyltetracycline and so this structure may be regarded as the minimum pharmacophore.

2. Features important for antibacterial activity among the tetracyclines are maintenance of the linear fused tetracycle, naturally occurring (α) stereochemical configurations at the 4a, 12a (A-B ring junction), and 4 (dimethylamino group) positions, and conservation of the keto-enol system (positions 11, 12, and 12a) in proximity to the phenolic D ring.

3. Chelation sites include the β-diketone system (positions 11 and 12) and the enol (positions 1 and 3) and carboxamide (position 2) groups of the A ring.

4. Replacement of the C-2 carboxamide moiety with other groups has generally resulted in analogs with inferior antibacterial activity, probably because bacteria accumulate these molecules poorly.

5. However, the addition of substituents to the amide nitrogen can impart significant water solubility, as in the case of rolitetracycline and lymecycline.

6. Consistent with the above observations, substitutions at positions 1, 3, 4a, 10, 11, or 12 are invariably detrimental for antibacterial activity.

7. A number of other substitutions at different positions on the B, C, and D rings are tolerated, and molecules possessing these substituents have given rise to the tetracyclines in clinical use today, as well as the new glycylcycline molecules that are currently undergoing clinical trials.

8. The extensive structure-activity studies referred to above revealed that with one exception, each of the rings in the linear fused tetracyclic nucleus must be six membered and purely carbocyclic for the molecules to retain antibacterial activity.

9. For instance, the nortetracyclines, derivatives in which the B ring comprises a five-membered carbocycle, are essentially devoid of antibacterial activity . Nevertheless, 6-thiatetracycline, which possesses a sulfur atom at position 6 of the C ring, is an apparent exception to the rule that a purely carbocyclic six-membered ring structure is required for activity, since molecules in this series have potent antibacterial properties.

Atypical tetracyclines:
These molecules, which also include the anhydrotetracyclines, 4-epi-anhydrotetracyclines, and chelocardin, appear to directly perturb the bacterial cytoplasmic membrane, leading to a bactericidal response (43, 198, 199). This contrasts with the typical tetracyclines, which interact with the ribosome to inhibit bacterial protein synthesis and display a reversible bacteriostatic effect. The membrane-disrupting properties of the atypical tetracyclines are probably related to the relative planarity of the B, C, and D rings so that a lipophilic, nonionized molecule predominates. On interaction with the cell, the atypical tetracyclines are likely to be preferentially trapped in the hydrophobic environment of the cytoplasmic membrane, disrupting its function. These molecules are of no interest as therapeutic candidates because they cause adverse side effects in humans (250), which are probably related to their ability to interact nonspecifically with eukaryotic as well as prokaryotic cell membranes.


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