Tetracyclines

Abstract

The 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 chlorotetracycline. 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 marketed tetracyclines were made by a semisynthetic pathway. The first of these were methacycline (6‐methylene oxytetracycline), and its reduction product doxycycline. The latest addition is minocycline. Minocycline showed superior antibacterial activity over other older tetracyclines and was active against many tetracycline‐resistant strains of gram‐positive bacteria when it was first discovered. In general, the tetracyclines are yellow crystalline compounds that have amphoteric properties. 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 of Streptomyces in a medium chosen to produce growth and maximum antibiotic production. Most of the clinically useful tetracyclines have been prepared either semi‐synthetically or isolated from fermentation. Tetracyclines inhibit bacterial growth by blocking protein synthesis and are bacteriostatic. The crystal structure of complex of Thermus thermophilius 30S ribosomal subunit with tetracycline has recently been determined. 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, and in the treatment of acne vulgaris and rosacea. Tetracyclines are used as alternative drugs in a variety of circumstances when 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. The discovery of glycylcyclines represents a significant advance in combating highly resistant organisms. One of the compounds, tigecycline, is current in phase III clinical trials. Tigecycline exhibits potent antibacterial activity against a broad‐spectrum of both tetracycline‐susceptible and tetracycline‐resistant organisms, including organisms resistant to other class of antibiotics. Most notably, it is active against multiply‐resistant staphylococci, vancomycin‐resistant enterococci, penicillin‐resistant streptococci and methicillin‐resistant S. aureous .