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]
This article is about the group of antibiotics known as the tetracyclines. For the specific antibiotic called "tetracycline", see tetracycline.
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]
Medical uses[edit]
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.[6][7] Tetracyclines are widely used in the treatment of moderately severe acne and rosacea (tetracycline, oxytetracycline, doxycycline or minocycline).[8] Anaerobic bacteria are not as susceptible to tetracyclines as are aerobic bacteria.[9] 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.[10] 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 (Lyme disease/borreliosis and syphilis).[2] They are also used in veterinary medicine.[2] They may have a role in reducing the duration and severity of cholera, although drug-resistance is mounting[11] and their effect on overall mortality is questioned.[12]
Mechanism of action[edit]
Tetracycline antibiotics are protein synthesis inhibitors.[22] They inhibit the initiation of translation in variety of ways by binding to the 30S ribosomal subunit, which is made up of 16S rRNA and 21 proteins. They inhibit the binding of aminoacyl-tRNA to the mRNA translation complex. Some studies have shown that tetracyclines may bind to both 16S and 23S rRNAs.[23] Tetracyclines also have been found to inhibit matrix metalloproteinases. This mechanism does not add to their antibiotic effects, but has led to extensive research on chemically modified tetracyclines or CMTs (like incyclinide) for the treatment of rosacea, acne, diabetes and various types of neoplasms.[24][25][26] It has been shown that tetracyclines are not only active against broad spectrum of bacteria, but also against viruses, protozoa that lack mitochondria and some noninfectious conditions. The binding of tetracyclines to cellular dsRNA (double stranded RNA) may be an explanation for their wide range of effect. It can also be attributed to the nature of ribosomal protein synthesis pathways among bacteria.[23] Incyclinide was announced to be ineffective for rosacea in September 2007.[27] Several trials have examined modified and unmodified tetracyclines for the treatment of human cancers; of those, very promising results were achieved with CMT-3 for patients with Kaposi Sarcoma.[28]
Structure-activity relationship[edit]
Tetracyclines are composed of a rigid skeleton of 4 fused rings.[2] The rings structure of tetracyclines is divided into an upper modifiable region and a lower non modifiable region.[29][30] An active tetracycline requires a C10 phenol as well as a C11-C12 keto-enol substructure in conjugation with a 12a-OH group and a C1-C3 diketo substructure.[2][30][29] Removal of the dimethylamine group at C4 reduces antibacterial activity.[30][29] Replacement of the carboxylamine group at C2 results in reduced antibacterial activity but it is possible to add substituents to the amide nitrogen to get more soluble analogs like the prodrug lymecycline.[2] The simplest tetracycline with measurable antibacterial activity is 6-deoxy-6-demethyltetracycline and its structure is often considered to be the minimum pharmacophore for the tetracycle class of antibiotics.[2][31] C5-C9 can be modified to make derivatives with varying antibacterial activity.[30][29]
Administration[edit]
When ingested, it is usually recommended that the more water-soluble, short-acting tetracyclines (plain tetracycline, chlortetracycline, oxytetracycline, demeclocycline and methacycline) be taken with a full glass of water, either two hours after eating or two hours before eating. This is partly because most tetracyclines bind with food and also easily with magnesium, aluminium, iron and calcium, which reduces their ability to be completely absorbed by the body. Dairy products, antacids and preparations containing iron should be avoided near the time of taking the drug. Partial exceptions to these rules occur for doxycycline and minocycline, which may be taken with food (though not iron, antacids, or calcium supplements). Minocycline can be taken with dairy products because it does not chelate calcium as readily, although dairy products do decrease absorption of minocycline slightly.[39]
Use as research reagents[edit]
Members of the tetracycline class of antibiotics are often used as research reagents in in vitro and in vivo biomedical research experiments involving bacteria as well in experiments in eukaryotic cells and organisms with inducible protein expression systems using tetracycline-controlled transcriptional activation.[61] The mechanism of action for the antibacterial effect of tetracyclines relies on disrupting protein translation in bacteria, thereby damaging the ability of microbes to grow and repair; however protein translation is also disrupted in eukaryotic mitochondria leading to effects that may confound experimental results.[62][63] It can be used as an artificial biomarker in wildlife to check if wild animals are consuming a bait that contains a vaccine or medication. Since it is fluorescent and binds to calcium, a UV lamp can be used to check if it is in a tooth pulled from an animal. For example, it was used to check uptake of oral rabies vaccine baits by raccoons in the USA. However, this is an invasive procedure for the animal and labour-intensive for the researcher. Therefore, other dyes such as rhodamine B that can be detected in hair and whiskers are preferred.[64]
