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. Tetracycline molecules comprise a linear fused tetracyclic nucleus (rings designated A, B, C and D) to which a variety of functional groups are attached. Tetracyclines are named for 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.While all tetracyclines have a common structure, they differ from each other by the presence of chloride, 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. 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. Tetracycline molecules comprise a linear fused tetracyclic nucleus (rings designated A, B, C and D) to which a variety of functional groups are attached. Tetracyclines are named for 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.While all tetracyclines have a common structure, they differ from each other by the presence of chloride, 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. Tetracyclines were discovered in the 1940s and exhibited activity against a wide range of microorganisms including gram-positive and gram-negative bacteria, chlamydiae, mycoplasmas, rickettsiae, and protozoan parasites. Tetracycline itself was discovered later than chlortetracycline and oxytetracycline but is still considered as the parent compound for nomenclature purposes.Tetracyclines are among the cheapest classes of antibiotics available and have been used extensively in the prophylaxis and therapy of human and animal infections, as well as at subtherapeutic levels in animals feed as growth promoters. Tetracyclines are inhibitors of growth (bacteriostatic) rather than killers of the infectious agent (bacteriocidal) and are only effective against multiplying microorganisms. 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. Tetracyclines retain an important role in medicine, although their usefulness has been reduced with the onset of antibiotic resistance. Tetracyclines remain the treatment of choice for some specific indications.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.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. Tetracyclines are generally used in the treatment of infections of the urinary tract, respiratory tract, and the intestines and are also used in the treatment of chlamydia, especially in patients allergic to β-lactams and macrolides; however, their use for these indications is less popular than it once was due to widespread development of resistance in the causative organisms.Tetracyclines are widely used in the treatment of moderately severe acne and rosacea (tetracycline, oxytetracycline, doxycycline or minocycline).Anaerobic bacteria are not as susceptible to tetracyclines as are aerobic bacteria.Doxycycline is also used as a prophylactic treatment for infection by Bacillus anthracis (anthrax) and is effective against Yersinia pestis, the infectious agent of bubonic plague. It is also used for malaria treatment and prophylaxis, as well as treating elephantitis filariasis.Tetracyclines remain the treatment of choice for infections caused by chlamydia (trachoma, psittacosis, salpingitis, urethritis and L. venereum infection), Rickettsia (typhus, Rocky Mountain spotted fever), brucellosis and spirochetal infections (borreliosis, syphilis and Lyme disease). They are also used in veterinary medicine.They may have a role in reducing the duration and severity of cholera, although drug-resistance is mounting and their effect on overall mortality is questioned. Side-effects from tetracyclines are not common, but of particular note is phototoxicity. It increases the risk of sunburn under exposure to light from the sun or other sources. This may be of particular importance for those intending to take on vacations long-term doxycycline as a malaria prophylaxis.They may cause stomach or bowel upsets, and, on rare occasions, allergic reactions. Very rarely, severe headache and vision problems may be signs of dangerous secondary intracranial hypertension, also known as idiopathic intracranial hypertension.Tetracyclines are teratogens due to the likelihood of causing teeth discolouration in the fetus as they develop in infancy. For this same reason, tetracyclines are contraindicated for use in children under 8 years of age. Some adults also experience teeth discoloration (mild grey hue) after use. They are, however, safe to use in the first 18 weeks of pregnancy.Some patients taking tetracyclines require medical supervision because they can cause steatosis and liver toxicity. Tetracyclines should be used with caution in those with liver impairment and those that are soluble in water and urine worsen renal failure (this is not true of the lipid-soluble agents doxycycline and minocycline). They may increase muscle weakness in myasthenia gravis and exacerbate systemic lupus erythematosus. Antacids containing aluminium and calcium reduce the absorption of all tetracyclines, and dairy products reduce absorption greatly for all but minocycline.The breakdown products of tetracyclines are toxic and can cause Fanconi syndrome, a potentially fatal disease affecting proximal tubular function in the nephrons of the kidney. Prescriptions of these drugs should be discarded once expired because they can cause hepatotoxicity.It was once believed that tetracycline antibiotics impair the effectiveness of many types of hormonal contraception. Recent research has shown no significant loss of effectiveness in oral contraceptives while using most tetracyclines. Despite these studies, many physicians still recommend the use of barrier contraception for people taking any tetracyclines to prevent unwanted pregnancy. Tetracycline use should be avoided in pregnant or lactating women, and in children with developing teeth because they may result in permanent staining (dark yellow-gray teeth with a darker horizontal band that goes across the top and bottom rows of teeth), and possibly affect the growth of teeth and bones.Usage during the first 12 weeks of pregnancy does not appear to increase the risk of any major birth defects. There may be a small increased risk for minor birth defects such as an inguinal hernia, but the number of reports is too small to be sure if there actually is any risk.In tetracycline preparation, stability must be considered in order to avoid formation of toxic epi-anhydrotetracyclines.