Tetracycline antibiotics
Tetracyclines are a group of
Tetracyclines were discovered in the 1940s and exhibited activity against a wide range of
Tetracyclines are growth inhibitors (
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
Medical uses
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
Tetracyclines are widely used in the treatment of moderately severe Anaerobic bacteria are not as susceptible to tetracyclines as are aerobic bacteria.[9]Side effects
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
Cautions
Tetracyclines should be used with caution by those with liver impairment. Also, because the molecules are soluble in water it can worsen
Contraindications
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.[21] 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.[21] In tetracycline preparation, stability must be considered in order to avoid formation of toxic epi-anhydrotetracyclines.[citation needed]
Mechanism of action
Tetracycline antibiotics are
Structure-activity relationship
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]
Mechanism of resistance
Cells can become
Inactivation is the rarest type of resistance,[32] where NADPH-dependent oxidoreductase, a class of antibiotic destructase, modifies the tetracycline antibiotic at their oxidative soft spot leading to an inactivation of the tetracycline antibiotic. For example, the oxireductase makes a modification on the C11a site of oxytetracycline. Both Mg2+ chelation and ribosome binding are required for the biological activity of oxytetracycline and the modification attenuate the binding, leading to inactivation of the oxytetracycline antibiotic.[5]
In the most common mechanism of reaction, efflux,[23] various resistance genes encode a membrane protein that actively pumps tetracycline out of the cell by exchanging a proton for a tetracycline cation complex. This exchange leads to a reduced cytoplasmic concentration of tetracycline.[33]
In ribosomal protection, a resistance gene encodes a protein that can have several effects, depending on what gene is transferred.[34] Twelve classes of ribosomal protection genes/proteins have been found.[35]
Possible mechanisms of action of these protective proteins include:
- blocking tetracyclines from binding to the ribosome[36]
- binding to the ribosome and distorting the structure to still allow t-RNA binding while tetracycline is bound[37]
- binding to the ribosome and dislodging tetracycline[36][38]
Administration
When ingested, it is usually recommended that the more
History
The history of the tetracyclines involves the collective contributions of thousands of dedicated researchers, scientists, clinicians, and business executives. Tetracyclines were discovered in the 1940s, first reported in scientific literature in 1948, and exhibited activity against a wide range of microorganisms. The first members of the tetracycline group to be described were chlortetracycline and oxytetracycline.
Research conducted by anthropologist George J. Armelagos and his team at Emory University showed that ancient Nubians from the post-Meroitic period (around AD 350) had deposits of tetracycline in their bones, detectable through analyses of cross-sections through ultraviolet light – the deposits are fluorescent, just as are modern ones. Armelagos suggested that this was due to ingestion of the local ancient beer (very much like the Egyptian beer[46]), made from contaminated stored grains.[47]
Development
Tetracyclines were noted for their broad spectrum antibacterial activity and were commercialized with clinical success beginning in the late 1940s to the early 1950s. The second-generation semisynthetic analogs and more recent third-generation compounds show the continued evolution of the tetracycline platform towards derivatives with increased potency as well as efficacy against tetracycline-resistant bacteria, with improved pharmacokinetic and chemical properties.[40] Shortly after the introduction of tetracycline therapy, the first tetracycline-resistant bacterial pathogen was identified. Since then, tetracycline-resistant bacterial pathogens have continued to be identified, limiting tetracycline's effectiveness in treatment of bacterial disease.[48]
Glycylcyclines and fluorocyclines are new classes of antibiotics derived from tetracycline.[49][50][48] These tetracycline analogues are specifically designed to overcome two common mechanisms of tetracycline resistance, namely resistance mediated by acquired efflux pumps and/or ribosomal protection. In 2005, tigecycline, the first member of a new subgroup of tetracyclines named glycylcyclines, was introduced to treat infections that are resistant to other antimicrobials.[51] Although it is structurally related to minocycline, alterations to the molecule resulted in its expanded spectrum of activity and decreased susceptibility to the development of resistance when compared with other tetracycline antibiotics. Like minocycline, tigecycline binds to the bacterial 30S ribosome, blocking the entry of transfer RNA. This ultimately prevents protein synthesis and thus inhibiting bacterial growth. However, the addition of an N,N,-dimethylglycylamido group at the 9 position of the minocycline molecule increases the affinity of tigecycline for the ribosomal target up to 5 times when compared with minocycline or tetracycline. This allows for an expanded spectrum of activity and decreased susceptibility to the development of resistance.[48] While tigecycline was the first tetracycline approved in over 20 years, other, newer versions of tetracyclines are currently in human clinical trials.[52]
List of tetracycline antibiotics
Antibiotic (INN) | Source[40] | Half-life[53] | Notes |
---|---|---|---|
Tetracycline | Naturally occurring | 6–8 hours (short) | |
Chlortetracycline | 6–8 hours (short) | ||
Oxytetracycline | 6–8 hours (short) | ||
Demeclocycline | 12 hours (intermediate) | ||
Lymecycline | Semi-synthetic | 6–8 hours (short) | |
Meclocycline | 6–8 hours (short) | (no longer marketed) | |
Methacycline |
12 hours (intermediate) | ||
Minocycline | 16+ hours (long) | ||
Rolitetracycline | 6–8 hours (short) | ||
Doxycycline | 16+ hours (long) | ||
Tigecycline | Glycecyclines | 16+ hours (long) | |
Eravacycline | Newer | 16+ hours (long) | (formerly known as TP-434) received FDA approval on August 27, 2018, for treatment of complicated intra-abdominal infections.[54] |
Sarecycline | 16+ hours (long) | (formerly known as WC 3035) received FDA approval on October 1, 2018, for treatment of moderate to severe | |
Omadacycline | 16+ hours (long) | (formerly known as PTK-0796 FDA approval on October 2, 2018, for treatment of community-acquired pneumonia[59] and acute skin and skin structure infections.[60]
|
Use as research reagents
Members of the tetracycline class of antibiotics are often used as research
It can be used as an artificialSee also
- Glycylcycline
- Eravacycline
- Tetracycline controlled transcriptional activation
- Animal Drug Availability Act 1996
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External links
- Media related to Tetracycline antibiotics at Wikimedia Commons