Tetracycline antibiotics

Tetracyclines are a group of broad-spectrum antibiotic compounds that have a common basic structure and are either isolated directly from several species of Streptomyces bacteria or produced semi-synthetically from those isolated compounds.^[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.^[2] Tetracyclines are named after their four ("tetra-") hydrocarbon rings ("-cycl-") derivation ("-ine"). They are defined as a subclass of polyketides, having an octahydrotetracene-2-carboxamide skeleton and are known as derivatives of polycyclic naphthacene carboxamide.^[3] While all tetracyclines have a common structure, they differ from each other by the presence of chloro, methyl, and hydroxyl groups. These modifications do not change their broad antibacterial activity, but do affect pharmacological properties such as half-life and binding to proteins in serum.^[1]

Tetracyclines were discovered in the 1940s and exhibited activity against a wide range of microorganisms including gram-positive and gram-negative bacteria, chlamydiota, mycoplasmatota, rickettsiae, and protozoan parasites.^[2] Tetracycline itself was discovered later than chlortetracycline and oxytetracycline but is still considered as the parent compound for nomenclature purposes.^[4] Tetracyclines are among the cheapest classes of antibiotics available and have been used extensively in prophylaxis and in treatment of human and animal infections, as well as at subtherapeutic levels in animal feed as growth promoters.^[2]

Tetracyclines are growth inhibitors (bacteriostatic) rather than killers of the infectious agent (bacteriocidal) and are only effective against multiplying microorganisms.^[1] They are short-acting and passively diffuse through porin channels in the bacterial membrane. They inhibit protein synthesis by binding reversibly to the bacterial 30S ribosomal subunit and preventing the aminoacyl tRNA from binding to the A site of the ribosome. They also bind to some extent the bacterial 50S ribosomal subunit and may alter the cytoplasmic membrane causing intracellular components to leak from bacterial cells.

Tetracyclines all have the same antibacterial spectrum, although there are differences in species' sensitivity to types of tetracyclines. Tetracyclines inhibit protein synthesis in both bacterial and human cells. Bacteria have a system that allows tetracyclines to be transported into the cell, whereas human cells do not. Human cells therefore are spared the effects of tetracycline on protein synthesis.^[1]

Tetracyclines retain an important role in medicine, although their usefulness has been reduced with the onset of antibiotic resistance.^[2] Tetracyclines remain the treatment of choice for some specific indications.^[2] Because not all of the tetracycline administered orally is absorbed from the gastrointestinal tract, the bacterial population of the intestine can become resistant to tetracyclines, resulting in overgrowth of resistant organisms. The widespread use of tetracyclines is thought to have contributed to an increase in the number of tetracycline-resistant organisms, in turn rendering certain infections more resilient to treatment.^[1] Tetracycline resistance is often due to the acquisition of new genes, which code for energy-dependent efflux of tetracyclines or for a protein that protects bacterial ribosomes from the action of tetracyclines. Furthermore, a limited number of bacteria acquire resistance to tetracyclines by mutations.^[2][5]