Tetracycline antibiotics

Tetracyclines are a group of broad-spectrum antibiotics 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". [GoldBookRef|title=tetracyclines|url=http://goldbook.iupac.org/T06287.html] They are collectively known as "derivatives of polycyclic naphthacene carboxamide".

History

The first member of the group to be discovered was Chlortetracycline (Aureomycin) in the late 1940s by 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 The Pharmaceutical Century] ] . 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 SAO/NASA ADS] ] . Robert Burns Woodward determined the structure of Oxytetracycline enabling Lloyd H. Conover to successfully produce tetracycline itself as a synthetic product [ [http://web.mit.edu/invent/iow/conover.html Inventor of the Week: Lloyd Conover] ] . The development of many chemically altered antibiotics formed this group. In June 2005, tigecycline, the first member of a new subgroup of tetracyclines named glycylcyclines was introduced to treat infections which are resistant to other antimicrobics including conventional tetracyclines [ [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1479133 PubMed Central: Functional, Biophysical, and Structural Bases for Antibacterial Activity of Tigecycline] ] . While tigecycline is the first tetracycline approved in over 20 years, other, newer versions of tetracyclines are currently in human clinical trials.Fact|date=February 2007

Mechanism of action

Tetracycline antibiotics inhibit protein synthesis by inhibiting the binding of aminoacyl-tRNA to the mRNA-ribosome complex. They do so mainly by binding to the 30S ribosomal subunit in the mRNA translation complex. [ [http://www.life-extension-drugs.com/doxycycline.html Life-Extension-Drugs.com - Doxycycline] ]

Tetracyclines also have been found to inhibit matrix metalloproteinases. This mechanism does not add to their antibiotic effects, but has lead to extensive research on chemically modified tetracyclines (like incyclinide) for the treatmet of rosacea, acne and various types of neoplasms. [cite journal
author = H. Spreitzer
date = July 2, 2007
title = Neue Wirkstoffe - Incyclinid
journal = Österreichische Apothekerzeitung
issue = 14/2007
pages = 655
language = German ] [cite journal
author = Viera, MH, Perez, OA, Berman, B
title = Incyclinide
journal = Drugs of the Future
volume = 32
issue = 3
pages = 209-214
url = http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=2&p_RefId=1083308&p_IsPs=N ] Since incyclinide was announced to be ineffective for rosacea in September 2007, no drugs of this group will be marketed in the near future. [ [http://www.reuters.com/article/companyNewsAndPR/idUSWEN127920070926 Reuters: CollaGenex says incyclinide ineffective for rosacea] ]

Mechanism and resistance

Tetracycline inhibits cell growth by inhibiting translation. It binds to the 16S part of the 30S ribosomal subunit and prevents the amino-acyl 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: 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 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 dislodging 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 β-lactams and macrolides; however, their use for these indications is less popular than it once was due to widespread resistance development in the causative organisms.

Their most common current use is in the treatment of moderately severe 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 "L. venereum" infection), Rickettsia (typhus, Rocky Mountain spotted fever), brucellosis, and spirochetal infections (borreliosis, syphilis, and Lyme disease). In addition, they may be used to treat anthrax, plague, tularemia, and Legionnaires' disease.

They may have a role in reducing the duration and severity of cholera, although drug-resistance is occurringcite 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 | pmid=12562304 | doi=10.1517/14656566.4.2.141] and their effects on overall mortality is questioned.cite journal | author=Parsi VK | title=Cholera | journal=Prim. Care Update Ob Gyns | year=2001 | pages=106–109 | volume=8 | issue=3 | pmid=11378428 | doi=10.1016/S1068-607X(00)00086-X]

Demeclocycline has an additional use in the treatment of 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, either two hours after eating or one hour before eating. This is partly because 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 absorption of tetracyclines.

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.

Previously, it was believed that tetracycline antibiotic impair the effectiveness of many types of hormonal contraception. Recent research has shown no significant loss of effectiveness in oral contraceptives while using most tetracycline antibiotic, with the exception of the drug rifampin. Despite these studies, many physicians still recommend the use of barrier contraception for people taking any tetracycline antibiotic to prevent unwanted pregnancy. [cite journal
last = Archer
first = JS
coauthors = Archer, DF
title = Oral contraceptive efficacy and antibiotic interaction: a myth debunked.
journal = Journal of the American Academy of Dermatology
volume = 46
issue = 6
pages = 917–23
date = Jun 2002
url = http://www.eblue.org/article/S0190-9622(02)00037-3/abstract
format = html
accessdate = 2008-04-04
doi = 10.1067/mjd.2002.120448 ] [cite journal
last = Dreno
first = Bridgitte
coauthors = et al
title = European recommendations on the use of oral antibiotics for acne
journal = European Journal of Dermatology
volume = 14
issue = 6
pages = 391–9
location = Berlin
date = Nov-Dec 2004
url = http://www.jle.com/en/revues/medecine/ejd/e-docs/00/04/07/1B/resume.md?type=text.html
format = html
accessdate = 2008-04-04 ] [cite journal
last = DeRossi
first = SS
coauthors = Hersh, EV
title = Antibiotics and oral contraceptives.
journal = Dental clinics of North America
volume = 46
issue = 4
pages = 653–64
date = Oct 2002
url = http://www.ncbi.nlm.nih.gov/pubmed/12436822
format = html
accessdate = 2008-04-04
doi = 10.1016/S0011-8532(02)00017-4 ]

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.

ide 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 secondary intracranial hypertension also known as Pseudotumor cerebri.

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 12 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. 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 | pmid=2609344 | doi=10.1016/0041-008X(89)90252-4] 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 | pmid=9441722 | doi=10.1006/faat.1997.2389] 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 | pmid=7151717 | doi=10.3109/01480548209041054]

Examples of tetracyclines

According to source:
*Naturally-occurring
**Tetracycline
**Chlortetracycline
**Oxytetracycline
**Demeclocycline
*Semi-synthetic
**Doxycycline
**Lymecycline
**Meclocycline
**Methacycline
**Minocycline
**Rolitetracycline

According to duration of action:
*Short-acting (Half-life is 6-8 hrs)
**Tetracycline
**Chlortetracycline
**Oxytetracycline
*Intermediate-acting (Half-life is ~12 hrs)
**Demeclocycline
**Methacycline
*Long-acting (Half-life is 16 hrs or more)
**Doxycycline
**Minocycline
**Tigecycline

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

References

ee also

*Glycylcycline
*Tetracycline controlled transcriptional activation