View source for Tetracycline antibiotics

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{{dablink|This article deals with the group of antibiotics known as the tetracyclines. For the specific antibiotic called “tetracycline,” see [[tetracycline]].}}

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[[Image:Tetracyclines.png|thumb|left|250px|The 4 rings of the basic tetracycline structure.]]
'''Tetracyclines''' are a group of [[broad-spectrum antibiotic]]s whose general usefulness has been reduced with the onset of bacterial resistance. Despite this, they remain the treatment of choice for some specific indications.

They are so named for their four (“tetra-”) [[hydrocarbon]] rings (“-cycl-”) derivation (“-ine”). More specifically, they are defined as "a subclass of polyketides having an octahydrotetracene-2-carboxamide skeleton".<ref>{{GoldBookRef|title=tetracyclines|url=http://goldbook.iupac.org/T06287.html}}</ref>

==History==
The first member of the group to be discovered was [[Chlortetracycline]] (Aureomycin) in the late 1940s by Benjamin Minge Duggar|Dr. Benjamin Duggar, a scientist employed by Lederle Laboratories who derived the substance from a golden-colored, fungus-like, soil-dwelling bacterium named ''Streptomyces aureofaciens''[http://pubs.acs.org/journals/pharmcent/Ch3.html]. [[Oxytetracycline]] (Terramycin) was discovered shortly afterwards by AC Finlay et al, it came from a similar soil bacterium named ''Streptomyces rimosus''[http://adsabs.harvard.edu/abs/1950Sci...111...85F]. Robert Burns Woodward determined the structure of Oxytetracycline enabling Lloyd Conover|Lloyd H. Conover to successfully produce [[tetracycline]] itself as a synthetic product[http://web.mit.edu/invent/iow/conover.html]. The development of many chemically altered antibiotics formed this group. In June 2005, [[tigecycline]], the first member of a new subgroup of tetracyclines named [[glycylcycline]]s was introduced to treat infections which are resistant to other antimicrobics including conventional tetracyclines[http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1479133]. While tigecycline is the first tetracycline approved in over 20 years, other, newer versions of tetracyclines are currently in human clinical trials.

==Examples of tetracyclines==
[[Image:Tetralysal.jpg|thumb|left|250px|[[Lymecycline]] (Tetralysal®) a member of the Tetracycline group of antibiotics]]
*Naturally-occurring
**[[Tetracycline]]
**[[Chlortetracycline]]
**[[Oxytetracycline]]
**[[Demeclocycline]]
*Semi-synthetic
**[[Doxycycline]]
**[[Lymecycline]]
**[[Meclocycline]]
**[[Methacycline]]
**[[Minocycline]]
**[[Rolitetracycline]]

[[Tigecycline]] may also be considered a tetracycline antibiotic, though it is usually classified as a [[glycylcycline]] antibiotic.

== Mechanism and resistance ==
Tetracycline inhibits cell growth by inhibiting [[translation (genetics)|translation]].  It binds to the 16S part of the 30S [[Ribosome|ribosomal]] subunit and prevents the amino-acyl [[Transfer RNA|tRNA]] from binding to the A site of the ribosome.  The binding is reversible in nature.

Cells become resistant to tetracycline by at least three mechanisms: [[enzyme|enzymatic]] inactivation of tetracycline, [[efflux]] and ribosomal protection.  Inactivation is the rarest type of resistance, where an [[acetyl group]] is added  to the molecule, causing inactivation of the drug.  In efflux, a resistance gene encodes a membrane protein that actively pumps tetracycline out of the cell.  This is the mechanism of action of the tetracycline resistance gene on the artificial [[plasmid]] [[pBR322]].  In ribosomal protection a resistance gene encodes a protein which can have several effects depending on what [[gene]] is transferred.  Six classes of ribosomal protection genes/proteins have been found, all with high sequence [[homology (biology)|homology]] suggesting a common evolutionary ancestor.  

Possible mechanisms of action of these protective proteins include: 
# blocking tetracyclines from binding to the ribosome, 
# binding to the ribosome and distorting the structure to still allow t-RNA binding while tetracycline is bound, and 
# binding to the ribosome and disloding tetracycline.  

All of these changes to ribosomes are reversible (non-covalent) because ribosomes isolated from both tetracycline resistant and susceptible organisms both bind tetracycline equally well ''[[in vitro]]''.

==Indication==
Tetracyclines may be used in the treatment of infections of the respiratory tract, sinuses, middle ear, urinary tract, intestines, and also [[gonorrhoea]], especially in patients allergic to [[Beta-lactam|β-lactams]] and [[macrolide]]s; however, their use for these indications is less popular than it once was due to widespread [[antibiotic resistance|resistance]] development in the causative organisms.

Their most common current use is in the treatment of moderately severe [[Acne vulgaris|acne]] and [[rosacea]] ([[tetracycline]], [[oxytetracycline]], [[doxycycline]] or [[minocycline]]).

[[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 [[elephantiasis]].

Tetracyclines remain the treatment of choice for infections caused by [[chlamydia]] ([[trachoma]], [[psittacosis]], [[salpingitis]], [[urethritis]] and [[Lymphogranuloma venereum|''L. venereum'' infection]]), [[Rickettsia]] ([[typhus]], [[Rocky Mountain spotted fever]]), [[brucellosis]], and [[spirochete|spirochetal infections]] ([[borreliosis]], [[syphilis]], and [[Lyme disease]]). In addition, they may be used to treat [[anthrax]], [[bubonic plague|plague]], [[tularemia]], and [[Legionellosis|Legionnaires' disease]].

They may have a role in reducing the duration and severity of [[cholera]], although drug-resistance is occurring<ref name="ExpertOpinPharmacother2003-Bhattacharya">{{cite journal | author=Bhattacharya SK, National Institute of Cholera and Enteric Diseases | title=An evaluation of current cholera treatment | journal=Expert Opin Pharmacother | year=2003 | pages=141-6 | volume=4 | issue=2 | id=PMID 12562304}}</ref> and their effects on overall mortality is questioned.<ref name="PrimCareUpdateObGyns2001-Parsi ">{{cite journal | author=Parsi VK | title=Cholera | journal=Prim. Care Update Ob Gyns | year=2001 | pages=106-109 | volume=8 | issue=3 | id=PMID 11378428}}</ref>

[[Demeclocycline]] has an additional use in the treatment of [[Syndrome of inappropriate antidiuretic hormone|SIADH]].

Tetracycline derivatives are currently being investigated for the treatment of certain inflammatory disorders.

==Administration==
When ingested, it is usually recommended that tetracyclines should be taken with a full glass of water two hours after eating, and one hour before eating. This is partly due to the fact that tetracycline binds easily with [[magnesium]], [[aluminium]], [[iron]], and [[calcium]], which reduces its ability to be completely absorbed by the body. Dairy products or preparations containing iron are not recommended directly after taking the drug.

==Cautions==
Tetracyclines should be used with caution in those with liver impairment and may worsen renal failure (except doxycycline and minocycline). They may increase muscle weakness in [[myasthenia gravis]] and exacerbate [[systemic lupus erythematosus]]. Antacids and milk reduce the absoption of tetracyclines.

Like many antibiotics, they decrease the effectiveness of birth control pills.

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, so expired prescriptions of these drugs should be discarded once expired.

==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.

==Side effects==
Side effects from tetracyclines are not always common, but of particular note is possible photosensitive allergic reaction which increases the risk of sunburn under exposure to UV light from the sun or other sources. This may be of particular importance for those intending to take on holidays long-term doxycyline as a malaria prophylaxis.

They may cause stomach or bowel upsets, and rarely allergic reactions. Very rarely severe headache and vision problems may be signs of dangerous [[Idiopathic intracranial hypertension|secondary intracranial hypertension]] also known as [[Pseudotumor cerebri]].

Tetracyclines are [[Teratogenesis|teratogens]] due to the likihood of causing [[Tooth#Discoloration|teeth discolouration]] in the foetus as they develop in infancy. For this same reason, tetracyclines are contraindicated for use in [[children]] under 8 years of age. 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 [[hepatotoxicity]]. <ref name="Deboysa-steatosis_1989">{{cite journal | author=Deboyser D, Goethals F, Krack G, Roberfroid M. | title=Investigation into the mechanism of tetracycline-induced steatosis: study in isolated hepatocytes. | journal=Toxicology and Applied Pharmacology | year=1989 | pages=473-9 | volume=97 | issue=3 | id=PMID 2609344}}</ref> <ref name="Amacher-caninesteatosis_1997">{{cite journal | author=Amacher DE, Martin BA. | title=Tetracycline-induced steatosis in primary canine hepatocyte cultures. | journal=Fundamental and Applied Toxicology | year=1997 | pages=256-63 | volume=40 | issue=2 | id=PMID 9441722}}</ref> <ref name="Ekwall-steatosis_1982">{{cite journal | author=Ekwall B, Acosta D. | title=In vitro comparative toxicity of selected drugs and chemicals in HeLa cells, Chang liver cells, and rat hepatocytes. | journal=Drug and Chemical Toxicology | year=1982 | pages=219-31 | volume=5 | issue=3 | id=PMID 7151717}}</ref>

==References==
<references/>
*[[British National Formulary]] ''49'' March 2005

==See also==
*[[Glycylcycline]]
*[[Tetracycline controlled transcriptional activation]]

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[[Category:Antibiotics]]
[[Category:Polyketide antibiotics]]
[[Category:Tetracycline antibiotics]]
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