Tetracyclines
Authors: Hlavka Joseph J. , Ellestad George A. , Chopra Ian 
Published: July 2004

AbstractThe tetracyclines are a group of antibiotics having an identical 4‐ring carbocyclic structure as a basic skeleton and differing from each other chemically only by substituent variation. The first tetracycline discovered was produced by a soil organism,Streptomyces aureofaciens, and is now known as chlortetracycline, C22H23ClN2O8. This compound ushered in a new era in antibacterial chemotherapy because it was effective orally and against a broad range of gram‐positive and gram‐negative bacteria. The three tetracyclines most recently marketed were made by a semisynthetic pathway. The first of these were methacycline (6‐methylene oxytetracycline), C22H22N2O8, and its reduction product doxycycline, C22H24ClN2O8. The most recent addition to the commercial tetracyclines is minocycline, C23H27N3O7. In general, the tetracyclines are yellow crystalline compounds that have amphoteric properties. They are soluble in both aqueous acid and aqueous base. The tetracyclines are strong chelating agents. This ability to chelate to metals, such as calcium, results in tooth discoloration when tetracycline is administered to children. Although many tetracycline derivatives showed usefulin vivoactivity against a wide spectrum of pathogenic organisms, few showed any significant improvement in overall activity when compared to tetracycline. The exception is minocycline which exhibits superior activity against tetracycline‐sensitive organisms and many tetracycline‐resistant strains of gram‐positive bacteria. Most of the fermentation and isolation processes for manufacture of the tetracyclines are described in patents. Manufacture begins with the cultivated growth of selected strains ofStreptomycesin a medium chosen to produce optimum growth and maximum antibiotic production. Some clinically useful tetracyclines are produced directly in these fermentations; others are produced by subjecting the fermentation products to one or more chemical alterations. The development of the semisynthetic β‐lactam antibiotics and emergence of resistance to the tetracyclines has steadily diminished the clinical usefulness of tetracyclines. Commercial tetracyclines and the corresponding trade names are chlortetracycline (Aureomycin), oxytetracycline (Terramycin), tetracycline (Achromycin), demeclocycline (Declomycin), methacycline (Rondomycin), doxycycline (Vibramycin), and minocycline (Minocin). Tetracyclines are accumulated by bacteria and prevent bacterial protein synthesis. Furthermore, inhibition of protein synthesis is responsible for the bacteriostatic effect. The emergence of bacterial resistance to tetracyclines has limited the use of these agents. Nevertheless, they are still the treatment of first choice for bacterial infections causing brucellosis, cholera, chancroid, granuloma inguinale, and Lyme disease; for rickettsial and chlamydial infections; in the treatment of nonspecific urethritis because ofChlamydiaorUreaplasmas; and in the treatment of acne vulgaris and rosacea. Tetracyclines are used as alternative drugs in a variety of circumstances when the patient is unable to take the drug of choice, eg, in patients allergic to penicillin. Tetracyclines are widely used for veterinary therapy. The types of pathogens encountered are frequently different from those for which tetracyclines are used in humans.