Doxycycline Vibramycin

Ball-and-Stick Model

Space-filling Model

Year of discovery: 1962 (Pfizer); Year of introduction: 1967 (as Vibramycin); Drug category: Tetracycline/broad-spectrum antibiotic; Main uses: For the treatment of respiratory tract, urinary tract and eye infections, anthrax, bubonic plague, syphilis, cholera, acne, gonorrhea, elephantiasis, and malaria; Other brand names: Adoxa, Doryx; Related drugs: Minocycline (Minocin), Lymecycline (Tetralysal), Demeclocycline (Declomycin).

The tetracycline class of broad-spectrum antibiotics, produced by soil-dwelling microbes of the Streptomyces family, are active against both Gram-positive and Gram-negative bacteria. The first members to be used in medicine were Chlortetracycline (from Lederle Laboratories) and Oxytetracycline (from Pfizer), both introduced in the early 1950s. They were followed by tetracycline, which was produced from Chlortetracycline by the chemical replacement of CI by H. All three became important in the treatment of bacterial infections because they are orally active against a wide variety of bacteria and very well-tolerated. Doxycycline, an improved synthetic tetracycline, was introduced by Pfizer in 1962 and became the most widely used member of the class.

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Chlortetracycline hjcoh ohh n|ch,)i

Oxytetracycline

Chlortetracycline

Oxytetracycline

Doxycycline is rapidly absorbed after oral administration, distributes to all important organs via blood (except the brain) and is well-tolerated by most people. With the exception of doxycycline, tetracyclines are excreted via the kidney. For this reason, doxycycline is the safest tetracycline for persons with impaired kidney function.

The antibiotic activity of tetracyclines is due to the selective inhibition of bacterial protein synthesis. Tetracyclines bind to the 30S subunit of the bacterial ribosome (the site of protein synthesis) and prevent the binding of amino-acyl f-RNA to the acceptor site (Asite) on the m-RNA-ribosome complex. As a result, protein synthesis is halted since no new amino acid can be delivered to the growing peptide chain. The pictures below shows tetracycline (TC, red) bound in the Asite of the 30S subunit. The close-up view below shows how the nucleoside residues (green) of the 30S subunit interact with the tetracycline molecule.1

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TC in the 30S Subunit

Close-Up View of TC

Tetracyclines are produced on a massive scale (over 30,000 tons/year). At one time tetracyclines were widely used to accelerate the growth of chickens and cattle. The emergence of resistant strains is only a matter of time when antibiotics are used on such a vast scale. Unfortunately, the discovery of entirely new antibiotics by microbial screening approaches has passed the point of diminishing returns. Biotarget structure-guided design and chemical modification of known antibiotics provide a way of dealing with resistant strains. Two examples of the application of this strategy to tetracyclines are shown below: (1) tigecycline (Wyeth, semisynthetic) and (2) pentacycline (AG. Myers, totally synthetic). Both are highly active against resistant strains.

Tigecycline (Tygacil )

Pentacycline

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