This article is about the group of antibiotics known as the tetracyclines. For the specific antibiotic called "tetracycline", see tetracycline.
The 4 rings of the basic tetracycline structure.
Tetracyclines are broad-spectrum antibiotics whose general usefulness has been reduced with the onset of antibiotic resistance. Despite this, they remain the treatment of choice for some specific indications.
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They are so named for their four ("tetra-") hydrocarbon rings ("-cycl-") derivation ("-ine"). To be specific, they are defined as "a subclass of polyketides having an octahydrotetracene-2-carboxamide skeleton".[1] They are collectively known as "derivatives of polycyclic naphthacene carboxamide".
Contents
- 1 Medical uses
- 2 Side effects
- 2.1 Cautions
- 2.2 Contraindications
- 3 Mechanism of action
- 4 Mechanism of resistance
- 5 Administration
- 6 History
- 7 Examples
- 7.1 Experimental tetracyclines in clinical trials
- 8 Use as a research reagent
- 9 See also
- 10 References
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 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.
Their most common current use is in the treatment of moderately severe acne and rosacea (tetracycline, oxytetracycline, doxycycline or minocycline).[citation needed]
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.[2]
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 are also used in veterinary medicine.
They may have a role in reducing the duration and severity of cholera, although drug-resistance is mounting[3] and their effect on overall mortality is questioned.[4]
Tetracycline derivatives are currently being investigated for the treatment of certain inflammatory disorders.
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 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 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.[5][6]
Some patients taking tetracyclines require medical supervision because they can cause steatosis and liver toxicity.[7][8][9]
Cautions
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.[10][11][12]
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.[13] 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.[13]
In tetracycline preparation, stability must be considered in order to avoid formation of toxic epi-anhydrotetracyclines.
Mechanism of action
Tetracycline antibiotics are protein synthesis inhibitors, 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.[14]
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.[15][16][17] Incyclinide was announced to be ineffective for rosacea in September 2007.[18]
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.[19]
Mechanism of 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 that 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
- 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 bind tetracycline equally well in vitro.
Administration
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.[20]
History
The first member of the group to be discovered is chlortetracycline (Aureomycin) in the late 1940s by Benjamin Minge Duggar, a scientist employed by American Cyanamid - Lederle Laboratories, under the leadership of Yellapragada Subbarow, who derived the substance from a golden-colored, fungus-like, soil-dwelling bacterium named Streptomyces aureofaciens.[21] Oxytetracycline (Terramycin) was discovered shortly afterwards by AC Finlay et al.; it came from a similar soil bacterium named Streptomyces rimosus.[22] Robert Burns Woodward determined the structure of oxytetracycline, enabling Lloyd H. Conover to successfully produce tetracycline itself as a synthetic product.[23] 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 that are resistant to other antimicrobics including conventional tetracyclines.[24] While tigecycline is the first tetracycline approved in over 20 years, other, newer versions of tetracyclines are currently in human clinical trials.[25]
A research conducted by anthropologist George J. Armelagos and his team at Emory University showed that ancient Nubians from the post-Meroitic period (around 350 CE) had deposits of tetracycline in their bones, detectable through analyses of cross sections through ultraviolet light - the deposits are fluorescent, just as modern ones. Armelagos suggested that this was due to ingestion of the local ancient beer (very much like the Egyptian beer[26]), made from contaminated stored grains.[27]
Examples
According to source:
- Naturally occurring
- Tetracycline
- Chlortetracycline
- Oxytetracycline
- Demeclocycline
- Semi-synthetic
- 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), allowing to be used one or twice daily only
- Doxycycline
- Minocycline
- Tigecycline
Tigecycline may also be considered a tetracycline antibiotic, though it is usually classified as a glycylcycline antibiotic.
Experimental tetracyclines in clinical trials
- Omadacycline (formerly known as PTK-0796[28]) in phase III clinical trials for Acute Bacterial Skin and Skin Structure Infections and Community Acquired Bacterial Pneumonia[29]
- Sarecycline (formerly known as WC 3035) in phase III clinical trials for Acne Vulgaris.[30]
Use as a research reagent
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. 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.[31][32]
See also
- Glycylcycline
- Tetracycline controlled transcriptional activation
- Animal Drug Availability Act 1996
References
- ^ IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) "tetracyclines".
- ^ http://www.eurekalert.org/pub_releases/2005-06/l-ats061505.php
- ^ Bhattacharya SK, National Institute of Cholera and Enteric Diseases (2003). "An evaluation of current cholera treatment". Expert Opin Pharmacother. 4 (2): 141–6. doi:10.1517/14656566.4.2.141. PMID 12562304.
- ^ Parsi VK (2001). "Cholera". Prim. Care Update Ob Gyns. 8 (3): 106–109. doi:10.1016/S1068-607X(00)00086-X. PMID 11378428.
- ^ http://www.tg.org.au/etg_demo/tgc/plg/5a58609.htm
- ^ https://docs.google.com/viewer?a=v&q=cache:pirPMTK4diYJ:www.aspenpharma.com.au/product_info/pi/PI_Achromycin.pdf+&hl=tr&gl=tr&pid=bl&srcid=ADGEESglhms2KnMNxqTQggqA1NFIZ5bCPuVLdnVkcqcQBZHQ7GvUg6eP_aE3BuPXrboyT3ww9GhDSuuuDWSY9l81b0HjWhxqheQ6K3oQVWtigcxfcKKhVfC7K-qDg-o_jKhPoG0DDjVj&sig=AHIEtbShF40Ty8nx5wadZwoCT_gqW8Ycww
- ^ Deboyser D, Goethals F, Krack G, Roberfroid M (1989). "Investigation into the mechanism of tetracycline-induced steatosis: study in isolated hepatocytes.". Toxicology and Applied Pharmacology. 97 (3): 473–9. doi:10.1016/0041-008X(89)90252-4. PMID 2609344.
- ^ Amacher DE, Martin BA (1997). "Tetracycline-induced steatosis in primary canine hepatocyte cultures.". Fundamental and Applied Toxicology. 40 (2): 256–63. doi:10.1006/faat.1997.2389. PMID 9441722.
- ^ Ekwall B, Acosta D (1982). "In vitro comparative toxicity of selected drugs and chemicals in HeLa cells, Chang liver cells, and rat hepatocytes.". Drug and Chemical Toxicology. 5 (3): 219–31. doi:10.3109/01480548209041054. PMID 7151717.
- ^ Archer JS, Archer DF (June 2002). "Oral contraceptive efficacy and antibiotic interaction: a myth debunked". Journal of the American Academy of Dermatology. 46 (6): 917–23. doi:10.1067/mjd.2002.120448. PMID 12063491.
- ^ Dréno B, Bettoli V, Ochsendorf F, Layton A, Mobacken H, Degreef H (2004). "European recommendations on the use of oral antibiotics for acne". European Journal of Dermatology. 14 (6): 391–9. PMID 15564203.
- ^ DeRossi SS, Hersh EV (October 2002). "Antibiotics and oral contraceptives". Dental clinics of North America. 46 (4): 653–64. doi:10.1016/S0011-8532(02)00017-4. PMID 12436822.
- ^ a b Tetracycline and Pregnancy from Organization of Teratology Information Specialists. July 2010.
- ^ Mechanism of Action of Tetracyclines
- ^ H. Spreitzer (July 2, 2007). "Neue Wirkstoffe - Incyclinid". Österreichische Apothekerzeitung (in German) (14/2007): 655.
- ^ Viera MH, Perez OA, Berman B (2007). "Incyclinide". Drugs of the Future. 32 (3): 209–214. doi:10.1358/dof.2007.032.03.1083308.
- ^ Ryan, M. E.; Usman, A.; Ramamurthy, N. S.; Golub, L. M.; Greenwald, R. A. (2001). "Excessive matrix metalloproteinase activity in diabetes: Inhibition by tetracycline analogues with zinc reactivity". Current medicinal chemistry. 8 (3): 305–316. doi:10.2174/0929867013373598. PMID 11172685.
- ^ Reuters: CollaGenex says incyclinide ineffective for rosacea
- ^ Richards, C.; Pantanowitz, L.; Dezube, B. J. (2011). "Antimicrobial and non-antimicrobial tetracyclines in human cancer trials". Pharmacological Research. 63 (2): 151–156. doi:10.1016/j.phrs.2010.10.008. PMID 20951804.
- ^ Piscitelli, Stephen C.; Keith Rodvold (2005). Drug Interactions in Infectious Diseases. Humana Press. ISBN 1-58829-455-2.
- ^ The Pharmaceutical Century
- ^ SAO/NASA ADS
- ^ Inventor of the Week: Lloyd Conover
- ^ Olson MW, Ruzin A, Feyfant E, Rush TS, O'Connell J, Bradford PA (June 2006). "Functional, biophysical, and structural bases for antibacterial activity of tigecycline". Antimicrobial Agents and Chemotherapy. 50 (6): 2156–66. doi:10.1128/AAC.01499-05. PMC 1479133. PMID 16723578.
- ^ http://www.bizjournals.com/boston/blog/bioflash/2015/10/how-paratek-hopes-to-succeed-in-antibiotics.html
- ^ SAMUEL, D. Archaeology of ancient Egypt beer. Journal of the American Society of Brewing Chemists, v. 54, n. 1, p. 3-12, 1996.
- ^ Bassett E. J.; Keith M. S.; Armelagos G. J.; Martin D. L.; Villanueva A. R. (1980). "Tetracycline-labeled human bone from ancient Sudanese Nubia (AD 350)" (PDF). Science. 209 (4464): 1532–1534. doi:10.1126/science.7001623.
- ^ http://www.bioworld.com/content/antibiotic-firm-paratek-joins-ipo-queue-aiming-92m-0
- ^ http://www.healio.com/infectious-disease/dermatology/news/online/%7Beb27007e-fe42-4b50-9da7-2bfc479c9366%7D/omadacycline-safe-effective-treatment-for-skin-infections
- ^ https://clinicaltrials.gov/ct2/show/NCT02320149
- ^ Moullan N, Mouchiroud L, Wang X, Ryu D, Williams EG, Mottis A, Jovaisaite V, Frochaux MV, Quiros PM, Deplancke B, Houtkooper RH, Auwerx J (2015). "Tetracyclines Disturb Mitochondrial Function across Eukaryotic Models: A Call for Caution in Biomedical Research.". Celll Reports. 10 (10): 1681–91. doi:10.1016/j.celrep.2015.02.034. PMID 25772356.
- ^ Chatzispyrou IA, Held NM, Mouchiroud L, Auwerx J, Houtkooper RH (2015). "Tetracycline antibiotics impair mitochondrial function and its experimental use confounds research.". Cancer Research. 72 (21): 4446–9. doi:10.1158/0008-5472.CAN-15-1626. PMID 26475870.
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Antibacterials: protein synthesis inhibitors (J01A, J01B, J01F, J01G, QJ01XQ)
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| 30S |
Aminoglycosides
(initiation inhibitors) |
| -mycin (Streptomyces) |
- Streptomycin#
- Dihydrostreptomycin
- Neomycin#
- Framycetin
- Paromomycin
- Ribostamycin
- Kanamycin#
- Amikacin
- Arbekacin
- Bekanamycin
- Dibekacin
- Tobramycin
- Spectinomycin#
- Hygromycin B
|
|
| -micin (Micromonospora) |
- Gentamicin#
- Netilmicin
- Sisomicin
- Plazomicin†
- Isepamicin
|
|
|
Tetracycline antibiotics
(tRNA binding) |
| Tetracyclines |
- Doxycycline#
- Chlortetracycline
- Clomocycline
- Demeclocycline
- Lymecycline
- Meclocycline
- Metacycline
- Minocycline
- Oxytetracycline
- Penimepicycline
- Rolitetracycline
- Tetracycline
|
|
| Glycylcyclines |
|
|
|
|
| 50S |
Oxazolidinone
(initiation inhibitors) |
- Eperezolid
- Linezolid
- Posizolid
- Radezolid
- Ranbezolid
- Sutezolid
- Tedizolid
|
|
| Peptidyl transferase |
| Amphenicols |
- Chloramphenicol#
- Azidamfenicol
- Thiamphenicol
- Florfenicol
|
|
| Pleuromutilins |
- Retapamulin
- Tiamulin
- Valnemulin
|
|
|
| MLS (transpeptidation/translocation) |
| Macrolides |
- Azithromycin#
- Clarithromycin
- Dirithromycin
- Erythromycin#
- Flurithromycin
- Josamycin
- Midecamycin
- Miocamycin
- Oleandomycin
- Rokitamycin
- Roxithromycin
- Spiramycin
- Troleandomycin
- Tylosin
- Ketolides
- Telithromycin
- Cethromycin
- Solithromycin†
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|
| Lincosamides |
- Clindamycin#
- Lincomycin
- Pirlimycin
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| Streptogramins |
- Pristinamycin
- Quinupristin/dalfopristin
- Virginiamycin
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| EF-G |
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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