Chemistry:Tetracycline

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Short description: Antibiotic used to treat a number of infections
Tetracycline
tetracycline 2D skeletal
tetracycline 3D BS
Clinical data
Pronunciation/ˌtɛtrəˈsaɪkliːn/
Other namesTE/TET/TC/TCY[1]
AHFS/Drugs.comMonograph
MedlinePlusa682098
License data
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability80%
MetabolismNot metabolized
Elimination half-life8–11 hours, 57–108 hours (kidney impairment)
ExcretionUrine (>60%), feces
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
Chemical and physical data
FormulaC22H24N2O8
Molar mass444.440 g·mol−1
3D model (JSmol)
  (verify)

Tetracycline, sold under various brand names, is an oral antibiotic in the tetracyclines family of medications, used to treat a number of infections,[3] including acne, cholera, brucellosis, plague, malaria, and syphilis.[3]

Common side effects include vomiting, diarrhea, rash, and loss of appetite.[3] Other side effects include poor tooth development if used by children less than eight years of age, kidney problems, and sunburning easily.[3] Use during pregnancy may harm the baby.[3] It works by inhibiting protein synthesis in bacteria.[3]

Tetracycline was patented in 1953[4] and was approved for prescription use in 1954.[5][6] It is on the World Health Organization's List of Essential Medicines.[7] Tetracycline is available as a generic medication.[3] Tetracycline was originally made from bacteria of the genus Streptomyces.[3]

Medical uses

Spectrum of activity

Tetracyclines have a broad spectrum of antibiotic action. Originally, they possessed some level of bacteriostatic activity against almost all medically relevant aerobic and anaerobic bacterial genera, both Gram-positive and Gram-negative, with a few exceptions, such as Pseudomonas aeruginosa and Proteus spp., which display intrinsic resistance. However, acquired (as opposed to inherent) resistance has proliferated in many pathogenic organisms and greatly eroded the formerly vast versatility of this group of antibiotics. Resistance amongst Staphylococcus spp., Streptococcus spp., Neisseria gonorrhoeae, anaerobes, members of the Enterobacteriaceae, and several other previously sensitive organisms is now quite common. Tetracyclines remain especially useful in the management of infections by certain obligately intracellular bacterial pathogens such as Chlamydia, Mycoplasma, and Rickettsia. They are also of value in spirochaetal infections, such as syphilis, and Lyme disease. Certain rare or exotic infections, including anthrax, plague, and brucellosis, are also susceptible to tetracyclines. Tetracycline tablets were used in the plague outbreak in India in 1994.[8] Tetracycline is first-line therapy for Rocky Mountain spotted fever (Rickettsia), Lyme disease (B. burgdorferi), Q fever (Coxiella), psittacosis, Mycoplasma pneumoniae, and nasal carriage of meningococci.[citation needed]

It is also one of a group of antibiotics which together may be used to treat peptic ulcers caused by bacterial infections. 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.[9][10]

The following list presents MIC susceptibility data for some medically significant microorganisms:

Anti-eukaryote use

The tetracyclines also have activity against certain eukaryotic parasites, including those responsible for diseases such as dysentery caused by an amoeba, malaria (a plasmodium), and balantidiasis (a ciliate).[citation needed]

Use as a biomarker

Tetracycline hydrochloride is available as yellow crystalline powder.

Since tetracycline is absorbed into bone, it is used as a marker of bone growth for biopsies in humans. Tetracycline labeling is used to determine the amount of bone growth within a certain period of time, usually a period around 21 days. Tetracycline is incorporated into mineralizing bone and can be detected by its fluorescence.[12] In "double tetracycline labeling", a second dose is given 11–14 days after the first dose, and the amount of bone formed during that interval can be calculated by measuring the distance between the two fluorescent labels.[13]

Tetracycline is also used as a biomarker in wildlife to detect consumption of medicine- or vaccine-containing baits.[14]

Side effects

Use of tetracycline antibiotics can:[15]

  • Discolor permanent teeth (yellow-gray-brown), from prenatal period through childhood and adulthood. Children receiving long- or short-term therapy with a tetracycline or glycylcycline may develop permanent brown discoloration of the teeth.
  • Be inactivated by calcium ions, so are not to be taken with milk, yogurt, and other dairy products
  • Be inactivated by aluminium, iron, and zinc ions, not to be taken at the same time as indigestion remedies (some common antacids and over-the-counter heartburn medicines)
  • Cause skin photosensitivity, so exposure to the sun or intense light is not recommended
  • Cause drug-induced lupus, and hepatitis
  • Cause microvesicular fatty liver
  • Cause tinnitus[16]
  • Interfere with methotrexate by displacing it from the various protein-binding sites
  • Cause breathing complications, as well as anaphylactic shock, in some individuals
  • Affect bone growth of the fetus, so should be avoided during pregnancy
  • Fanconi syndrome may result from ingesting expired tetracyclines.

Caution should be exercised in long-term use when breastfeeding. Short-term use is safe; bioavailability in milk is low to nil.[17] According to the U.S. Food and Drug Administration (FDA), cases of Stevens–Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme associated with doxycycline use have been reported, but a causative role has not been established.[18]

Pharmacology

Mechanism of action

Tetracycline inhibits protein synthesis by blocking the attachment of charged tRNA at the P site peptide chain. Tetracycline blocks the A-site so that a hydrogen bond is not formed between the amino acids. Tetracycline binds to the 30S and 50S subunit of microbial ribosomes.[3] Thus, it prevents the formation of a peptide chain.[19] The action is usually not inhibitory and irreversible even with the withdrawal of the drug. Mammalian cells are less vulnerable to the effect of tetracyclines, despite the fact that tetracycline binds to the small ribosomal subunit of both prokaryotes and eukaryotes (30S and 40S, respectively). This is because bacteria actively pump tetracycline in, even against a concentration gradient[dubious – discuss], whereas mammalian cells are simply not affected by the mechanisms of tetracycline within the cytoplasm. This accounts for the relatively small off-site effect of tetracycline on human cells.[20]

Mechanisms of resistance

Bacteria usually acquire resistance to tetracycline from horizontal transfer of a gene that either encodes an efflux pump or a ribosomal protection protein. Efflux pumps actively eject tetracycline from the cell, preventing the build up of an inhibitory concentration of tetracycline in the cytoplasm.[21] Ribosomal protection proteins interact with the ribosome and dislodge tetracycline from the ribosome, allowing for translation to continue.[22]

History

Discovery

The tetracyclines, a large family of antibiotics, were discovered by Benjamin Minge Duggar in 1948 as natural products, and first prescribed in 1948.[23] Benjamin Duggar, working under Yellapragada Subbarow at Lederle Laboratories, discovered the first tetracycline antibiotic, chlortetracycline (Aureomycin), in 1945.[24] The structure of Aureomycin was elucidated in 1952 and published in 1954 by the Pfizer-Woodward group.[25] After the discovery of the structure, researchers at Pfizer began chemically modifying aureomycin by treating it with hydrogen in the presence of a palladized carbon catalyst. This chemical reaction replaced a chlorine moiety with a hydrogen, creating a compound named tetracycline via hydrogenolysis.[26] Tetracycline displayed higher potency, better solubility, and more favorable pharmacology than the other antibiotics in its class, leading to its FDA approval in 1954. The new compound was one of the first commercially successful semi-synthetic antibiotics that was used, and laid the foundation for the development of Sancycline, Minocycline, and later the Glycylcyclines.[5]

Evidence in antiquity

Tetracycline has a high affinity for calcium and is incorporated into bones during the active mineralization of hydroxyapatite. When incorporated into bones, tetracycline can be identified using ultraviolet light.[27]

There is evidence that early inhabitants of Northeastern Africa consumed tetracycline antibiotics. Nubian mummies from between 350 and 550 A.D. were found to exhibit patterns of fluorescence identical with that of modern tetracycline labelled bone.[28]

It is conjectured that the beer brewed by the Nubians was the source of the tetracycline found in these bones.[29]

Society and culture

Price

According to data from EvaluatePharma and published in the Boston Globe, in the USA the price of tetracycline rose from $0.06 per 250-mg pill in 2013 to $4.06 a pill in 2015.[30] The Globe described the "big price hikes of some generic drugs" as a "relatively new phenomenon" which has left most pharmacists "grappling" with large upswings" in the "costs of generics, with 'overnight' price changes sometimes exceeding 1,000%."[30]

Names

It is marketed under the brand names Sumycin, Tetracyn, and Panmycin, among others. Actisite is a thread-like fiber formulation used in dental applications.[citation needed]

It is also used to produce several semisynthetic derivatives, which together are known as the tetracycline antibiotics. The term "tetracycline" is also used to denote the four-ring system of this compound; "tetracyclines" are related substances that contain the same four-ring system.[citation needed]

Media

Due to the drug's association with fighting infections, it serves as the main "commodity" in the science fiction series Aftermath, with the search for tetracycline becoming a major preoccupation in later episodes.[31]

Tetracycline is also represented in Bohemia Interactive's survival sandbox, DayZ. In the game, players may find the antibiotic to treat the common cold, influenza, cholera and infected wounds, but does not portray any side effects associated with tetracycline.

Research

Genetic engineering

In genetic engineering, tetracycline is used in transcriptional activation. It has been used as an engineered "control switch" in chronic myelogenous leukemia models in mice. Engineers were able to develop a retrovirus that induced a particular type of leukemia in mice, and could then "switch" the cancer on and off through tetracycline administration. This could be used to grow the cancer in mice and then halt it at a particular stage to allow for further experimentation or study.[32]

A technique being developed for the control of the mosquito species Aedes aegypti (the infection vector for yellow fever, dengue fever, Zika fever, and several other diseases) uses a strain that is genetically modified to require tetracycline to develop beyond the larval stage. Modified males raised in a laboratory develop normally as they are supplied with this chemical and can be released into the wild. Their subsequent offspring inherit this trait, but find no tetracycline in their environments, so never develop into adults.[33]

References

  1. ↑ "Antibiotic abbreviations list". https://microbiologie-clinique.com/antibiotic-family-abbreviation.html. 
  2. ↑ Template:Cite PubChem
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 "Tetracycline". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/tetracycline.html. 
  4. ↑ U.S. Patent 2,699,054A
  5. ↑ 5.0 5.1 "The history of the tetracyclines". Annals of the New York Academy of Sciences 1241 (1): 17–32. December 2011. doi:10.1111/j.1749-6632.2011.06354.x. PMID 22191524. Bibcode: 2011NYASA1241...17N. 
  6. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 489. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA489. 
  7. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  8. ↑ Lippincott's Illustrated Reviews: Pharmacology, 4th ed. Harvery RA, Champe, PC. Lippincott, Williams & Wilkins, 2009
  9. ↑ "Tetracyclines Disturb Mitochondrial Function across Eukaryotic Models: A Call for Caution in Biomedical Research". Cell Reports 10 (10): 1681–1691. March 2015. doi:10.1016/j.celrep.2015.02.034. PMID 25772356. 
  10. ↑ "Tetracycline antibiotics impair mitochondrial function and its experimental use confounds research". Cancer Research 75 (21): 4446–4449. November 2015. doi:10.1158/0008-5472.CAN-15-1626. PMID 26475870. 
  11. ↑ "Tetracycline hydrochloride". Susceptibility and Minimum Inhibitory Concentration (MIC) Data. TOKU-E. 8 September 2015. http://www.toku-e.com/Assets/MIC/Tetracycline%20hydrochloride.pdf. 
  12. ↑ "Tetracycline labeling of bone". http://www.histosearch.com/histonet/Dec02/TetracyclinelabelingofbonA.html. 
  13. ↑ "Tetracycline Labeling". The Johns Hopkins Medical Institutions.. 8 January 2001. http://pathology2.jhu.edu/bonelab/4cycline.htm. 
  14. ↑ "Bait ingestion by free-ranging raccoons and nontarget species in an oral rabies vaccine field trial in Florida". Journal of Wildlife Diseases 36 (4): 734–743. October 2000. doi:10.7589/0090-3558-36.4.734. PMID 11085436. http://www.jwildlifedis.org/cgi/reprint/36/4/734. 
  15. ↑ "Tetracycline: MedlinePlus Drug Information" (in en). https://medlineplus.gov/druginfo/meds/a682098.html. 
  16. ↑ Antibiotics Manual : A Guide to Commonly Used Antimicrobials. John Wiley & Sons, Inc.. 2017. pp. 367. 
  17. ↑ Breastfeeding and Human Lactation. Jones & Bartlett Learning. November 2010. p. 179. 
  18. ↑ "FDA Adverse Events Reporting System". 27 August 2010. https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm223734.htm. 
  19. ↑ "Mechanism of Action of Tetracyclines". Pharmaxchange.info. 2011-05-27. http://pharmaxchange.info/press/2011/05/mechanism-of-action-of-tetracyclines/. 
  20. ↑ "Antimicrobial Agents in the Treatment of Infectious Disease.". Todars Online Text Book of Bacteriology. 2012. http://textbookofbacteriology.net/antimicrobial_4.html. Retrieved 2013-08-27. 
  21. ↑ "Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance". Microbiology and Molecular Biology Reviews 65 (2): 232–60 ; second page, table of contents. June 2001. doi:10.1128/MMBR.65.2.232-260.2001. PMID 11381101. 
  22. ↑ "Ribosomal protection proteins and their mechanism of tetracycline resistance". Antimicrobial Agents and Chemotherapy 47 (12): 3675–3681. December 2003. doi:10.1128/AAC.47.12.3675-3681.2003. PMID 14638464. 
  23. ↑ "Chemistry and chemical biology of tetracyclines". http://www.chm.bris.ac.uk/motm/tetracycline/tetracycline.htm.  [better source needed]
  24. ↑ "Some historical notes on chlortetracycline". Reviews of Infectious Diseases 7 (5): 702–707. 1985. doi:10.1093/clinids/7.5.702. PMID 3903946. 
  25. ↑ "The Structure of Aureomycin 1" (in en). Journal of the American Chemical Society 76 (13): 3568–3575. July 1954. doi:10.1021/ja01642a064. ISSN 0002-7863. https://pubs.acs.org/doi/abs/10.1021/ja01642a064. 
  26. ↑ "Terramycin. Xi. Tetracycline" (in en). Journal of the American Chemical Society 75 (18): 4622–4623. September 1953. doi:10.1021/ja01114a537. ISSN 0002-7863. https://pubs.acs.org/doi/abs/10.1021/ja01114a537. 
  27. ↑ "Characterization of eight different tetracyclines: advances in fluorescence bone labeling". Journal of Anatomy 217 (1): 76–82. July 2010. doi:10.1111/j.1469-7580.2010.01237.x. PMID 20456523. 
  28. ↑ "Tetracycline-labeled human bone from ancient Sudanese Nubia (A.D. 350)". Science 209 (4464): 1532–1534. September 1980. doi:10.1126/science.7001623. PMID 7001623. Bibcode: 1980Sci...209.1532B. 
  29. ↑ "Take Two Beers and Call Me in 1,600 Years: Use of Tetracycline by Nubians and Ancient Egyptians". Natural History 109 (4): 50–53. 2000. 
  30. ↑ 30.0 30.1 "As competition wanes, prices for generics skyrocket". Boston Globe. 6 November 2015. https://www.bostonglobe.com/business/2015/11/06/generic-drug-price-increases-alarm-insurers-providers-and-consumers/H3iA9CSxAUylnCdGjLNKVN/story.html?event=event25. 
  31. ↑ "Aftermath Episode Recap". https://www.syfy.com/aftermath/episodes/season/2016/episode/9/the-barbarous-king. 
  32. ↑ "Rapid generation of a tetracycline-inducible BCR-ABL defective retrovirus using a single autoregulatory retroviral cassette". Leukemia 15 (10): 1658–1662. October 2001. doi:10.1038/sj.leu.2402225. PMID 11587226. 
  33. ↑ "Can GM mosquitoes rid the world of a major killer?". The Observer. 15 July 2012. https://www.theguardian.com/environment/2012/jul/15/gm-mosquitoes-dengue-fever-feature. 

External links



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