View source for Oxytetracycline

{{short description|Antibiotic}}
{{infobox drug
| verifiedrevid = 464196886
| IUPAC_name = (4''S'',4a''R'',5''S'',5a''R'',6''S'',12a''S'')-4-(Dimethylamino)-3,5,6,10,11,12a-hexahydroxy-6-methyl-1,12-dioxo-1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide
| image = Oxytetracycline.svg
| image2 = Oxytetracycline-from-xtal-Mercury-3D-balls.png

<!--Clinical data-->
| tradename = Terramycin
| Drugs.com =
| licence_US =
| pregnancy_AU = D
| pregnancy_category =
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->
| legal_US =
| legal_status = Rx-only
| routes_of_administration = [[Oral administration|By mouth]], [[Topical medication|topical]] ([[eye drop]])
| ATC_prefix = D06
| ATC_suffix = AA03
| ATC_supplemental = {{ATC|A01|AB25}}, {{ATC|G01|AA07}}, {{ATC|J01|AA06}}, {{ATC|S01|AA04}}, {{ATCvet|A01|AB25}}, {{ATCvet|J51|AA06}}

<!--Pharmacokinetic data-->
| bioavailability =
| protein_bound =
| metabolism =
| elimination_half-life = 6–8 hours
| excretion = [[Kidney]]

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 79-57-2
| PubChem= 54675779
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00595
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 10482174
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = SLF0D9077S
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = C06624
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 27701
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1517
| PDB_ligand = OAQ
| synonyms =

<!--Chemical data-->
| C=22 | H=24 | N=2 | O=9
| smiles = CN(C)[C@@H]3C(\O)=C(\C(N)=O)C(=O)[C@@]4(O)C(/O)=C2/C(=O)c1c(cccc1O)[C@@](C)(O)[C@H]2[C@H](O)[C@@H]34
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C22H24N2O9/c1-21(32)7-5-4-6-8(25)9(7)15(26)10-12(21)17(28)13-14(24(2)3)16(27)11(20(23)31)19(30)22(13,33)18(10)29/h4-6,12-14,17,25,27-29,32-33H,1-3H3,(H2,23,31)/t12-,13-,14+,17+,21-,22+/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = IWVCMVBTMGNXQD-PXOLEDIWSA-N
| melting_point = 181
| melting_high = 182
<!-- param not supported: | Isoelectric point = Approx 5.4 (ref:J. Chem. Soc. Pak., Vol. 35, No.1, 2013) -->
}}

'''Oxytetracycline''' is a [[broad-spectrum antibiotic|broad-spectrum]] [[tetracycline antibiotics|tetracycline antibiotic]], the second of the group to be discovered.

Oxytetracycline works by interfering with the ability of bacteria to produce essential proteins. Without these proteins, the bacteria cannot grow, multiply and increase in numbers. Oxytetracycline therefore stops the spread of the infection, and the remaining bacteria are killed by the immune system or eventually die.

Oxytetracycline is active against a wide variety of bacteria. However, some strains of bacteria have developed resistance to this antibiotic, which has reduced its effectiveness for treating some types of infections.

Oxytetracycline is used to treat infections caused by ''[[Chlamydia infection|Chlamydia]]'', such as [[psittacosis]], [[trachoma]], and [[urethritis]], and infections caused by ''[[Mycoplasma]]'' organisms, such as [[walking pneumonia|pneumonia]].

Oxytetracycline is used to treat [[acne]], due to its activity against the bacteria on the skin that influence the development of acne (''[[Cutibacterium acnes]]''). It is used to treat flare-ups of [[chronic bronchitis]], due to its activity against ''[[Haemophilus influenzae]]''. Oxytetracycline may be used to treat other rarer infections, such as those caused by a group of microorganisms called [[rickettsiae]] (e.g., [[Rocky Mountain spotted fever]]). To make sure the bacteria causing an infection are susceptible to it, a tissue sample is usually taken; for example, a swab from the infected area or a urine or blood sample.{{citation needed|date=January 2024}}

Oxytetracycline was patented in 1949 and came into commercial use in 1950.<ref>{{Cite book |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA489 |title=Analogue-based Drug Discovery |vauthors=Fischer J, Ganellin CR |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=489 |language=en}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]] as an alternative to [[tetracycline]].<ref name="WHO22nd">{{Cite book |author-link=World Health Organization |title=World Health Organization model list of essential medicines: 22nd list (2021) |vauthors=((World Health Organization)) |publisher=World Health Organization |year=2021 |location=Geneva |hdl=10665/345533 |id=WHO/MHP/HPS/EML/2021.02 |hdl-access=free}}</ref>

==Medical uses==
Oxytetracycline, like other [[tetracycline antibiotics|tetracyclines]], is used to treat many infections, both common and rare. Its better absorption profile makes it preferable to tetracycline for moderately severe [[Acne vulgaris|acne]] at a dosage of 250–500&nbsp;mg four times a day for usually six to eight weeks at a time, but alternatives should be sought if no improvement occurs by three months.<ref>[[British National Formulary]] ''45'' March 2003</ref>

It is sometimes used to treat [[spirochaetal]] infections, [[clostridial]] wound infection, and [[anthrax]] in patients sensitive to [[penicillin]]. Oxytetracycline is used to treat infections of the respiratory and urinary tracts, skin, ear, eye and [[gonorrhoea]], although its use for such purposes has declined in recent years due to large increases in [[bacterial resistance]] to this class of drugs. The drug is particularly useful when penicillins and/or [[macrolide]]s cannot be used due to allergy. It may be used to treat [[Legionnaires' disease]] as a substitute for a macrolide or [[Quinolone antibiotic|quinolones]].

Oxytetracycline is especially valuable in treating nonspecific urethritis,<!--unabbreviate LGV,--> [[Lyme disease]], [[brucellosis]], [[cholera]], <!-- disambig. Plague,--> [[typhus]], <!-- brucellosis? Relapsing Fever,--> [[tularaemia]], and infections caused by ''Chlamydia, Mycoplasma'', and ''Rickettsia''. Doxycycline is now preferred to oxytetracycline for many of these indications because it has improved pharmacologic features.{{clarify|date=January 2024}}

The standard dose is 250 to 500&nbsp;mg every six hours by mouth. In particularly severe infections, this dose may be increased accordingly. Occasionally, oxytetracycline is given by [[intramuscular]] injection or [[topical]]ly in the form of creams, ophthalmic [[ointment]]s, or eye drops.

== Side effects ==
Side effects are mainly gastrointestinal and [[photosensitivity|photosensitive]] allergic reactions common to the [[tetracycline antibiotics]] group. It can damage calcium-rich organs, such as teeth and bones, although this is very rare. It sometimes causes nasal cavities to erode; because of this, tetracyclines should not be used to treat pregnant or lactating women and children under age twelve except in certain conditions where it has been approved by a specialist because there are no obvious substitutes.{{citation needed|date=January 2024}} [[Candidiasis]] (thrush) is not uncommon following treatment with broad-spectrum antibiotics.

== History ==
[[File:Bottle of Terramycin with original contents and original car Wellcome L0058544.jpg|thumb|Pfizer-brand Terramycin for [[:wikt:otic|otic]] use, as sold in the UK, circa 1965]]
It was first found near [[Pfizer]] laboratories in a soil sample yielding the then{{Non breaking hyphen}}new [[actinomycete]] ''[[Streptomyces rimosus]]'' by Finlay ''et al.''<ref>Finlay, A. C., and others: Terramycin, a New Antibiotic, Science 111: 85 (27 January 1950)</ref>  In 1950, a group at Pfizer led by Francis A. Hochstein, working in a loose collaboration with the Harvard [[organic chemist]] [[Robert B. Woodward]], worked out the chemical structure of oxytetracycline, enabling Pfizer to [[mass production|mass-produce]] the drug under the trade name Terramycin.<ref name="pmid15428258">{{Cite journal |vauthors=Melcher GW, Gibson CD, Rose HM, Kneeland Y |date=August 1950 |title=Terramycin in the treatment of pneumococcic and primary atypical pneumonia |journal=Journal of the American Medical Association |volume=143 |issue=15 |pages=1303–8 |doi=10.1001/jama.1950.02910500005002 |pmid=15428258}}</ref><ref name="pmid20522541">{{Cite journal |vauthors=Pickens LB, Tang Y |date=September 2010 |title=Oxytetracycline biosynthesis |journal=The Journal of Biological Chemistry |volume=285 |issue=36 |pages=27509–15 |doi=10.1074/jbc.R110.130419 |pmc=2934616 |pmid=20522541 |doi-access=free}}</ref> This discovery was a major advancement in tetracycline research and paved the way for the discovery of an oxytetracycline derivative, [[doxycycline]], which is one of the most popularly used antibiotics today.<ref name="pmid20522541" />

== Biosynthesis ==
Oxytetracycline belongs to a structurally diverse class of aromatic [[polyketide]] antibiotics, also known as bacterial aromatic polyketides, produced by ''[[Streptomyces]]'' via type II [[polyketide synthases]] (PKSs).<ref>{{Cite book |title=Chemistry of Plant Natural Products |vauthors=Talapatra SK, Talapatra B |date=2015 |publisher=Springer |isbn=978-3-642-45410-3 |location=Berlin, Heidelberg |pages=679–715 |chapter=Polyketide Pathway. Biosynthesis of Diverse Classes of Aromatic Compounds |doi=10.1007/978-3-642-45410-3_14}}</ref> Other compounds produced via type II PKSs are important bioactive compounds ranging from anticancer agents like [[doxorubicin]] to antibiotics such as [[tetracycline]]. The biosynthesis of oxytetracycline can be broken down into three general portions:<ref name="pmid20522541" /> first is the formation of an amidated polyketide backbone with minimal [[polyketide synthases]] (PKSs), second is the cyclization of the polyketide backbone, and finally, the formation of anhydrotetracycline—a shared intermediate with tetracycline—to produce oxytetracycline.

The biosynthesis of oxytetracycline begins with the utilization of PKS enzymes [[ketosynthase]] (KS), the chain length factor (CLF), the [[acyl carrier protein]] (ACP), and an [[acyltransferase]] (encoded as ''OxyA'', ''OxyB'', ''OxyC'' and ''OxyP'' in the oxytetracycline [[gene cluster]])<ref>{{Cite journal |vauthors=Zhang W, Ames BD, Tsai SC, Tang Y |date=April 2006 |title=Engineered biosynthesis of a novel amidated polyketide, using the malonamyl-specific initiation module from the oxytetracycline polyketide synthase |journal=Applied and Environmental Microbiology |volume=72 |issue=4 |pages=2573–2580 |bibcode=2006ApEnM..72.2573Z |doi=10.1128/AEM.72.4.2573-2580.2006 |pmc=1449064 |pmid=16597959}}</ref> to [[catalysis|catalyze]] the extension of the malonamyl-CoA starting unit with eight [[malonyl-CoA]] extender units. The process of elongating the polypeptide skeleton occurs through a series of [[Claisen condensation|Claisen]]-like [[decarboxylation]] reactions until the linear tetracyclic skeleton is formed.<ref>{{Cite journal |vauthors=Tang Y, Tsai SC, Khosla C |date=October 2003 |title=Polyketide chain length control by chain length factor |journal=Journal of the American Chemical Society |volume=125 |issue=42 |pages=12708–09 |bibcode=2003JAChS.12512708T |doi=10.1021/ja0378759 |pmid=14558809}}</ref> Thus, minimal PKSs form a completed [[Amide|amidated]] polyketide backbone without any additional post-synthase tailoring enzymes (Figure 1).

[[File:Biosynthesis of the Amidated Polyketide Backbone.png|alt=|thumb|center|upright=3|Figure 1. The oxytetracycline gene cluster extends the malonamyl-CoA starting unit with 8 × malonyl-CoA to form an amidated polyketide backbone en route to Oxytetracycline.]]

Following the formation of the linear tetracyclic skeleton, four successive [[cyclization]] reactions must occur in a [[regioselective]] manner to produce the [[aromatic]] natural product known as pretetramid, a common precursor to both oxytetracycline and other tetracycline antibiotics.<ref>{{Cite journal |vauthors=McCormick JR, Johnson S |date=June 1, 1963 |title=Biosynthesis of the Tetracyclines. V. Naphthacenic Precursors |journal=Journal of the American Chemical Society |volume=85 |issue=11 |pages=1692–1694 |bibcode=1963JAChS..85.1692M |doi=10.1021/ja00894a037}}</ref> In the oxytetracycline gene cluster, these enzymes are encoded as ''OxyK'' ([[aromatase]]), ''OxyN'' ([[cyclase]]), and ''OxyI'' (cyclase).<ref>{{Cite journal |vauthors=Zhang W, Watanabe K, Wang CC, Tang Y |date=August 2007 |title=Investigation of early tailoring reactions in the oxytetracycline biosynthetic pathway |journal=The Journal of Biological Chemistry |volume=282 |issue=35 |pages=25717–25725 |doi=10.1074/jbc.M703437200 |pmid=17631493 |doi-access=free}}</ref> Formation of pretetramid allows for one of the most important intermediates en route to the biosynthesis of oxytetracycline; this is the generation of anhydrotetracycline.<ref>[https://pubchem.ncbi.nlm.nih.gov/compound/Anhydrotetracycline "Anhydrotetracycline"].</ref>{{full citation needed|date=November 2023}} Anhydrotetracycline contains the first functionalized [[Tetracycline antibiotics|A ring]] in this biosynthetic pathway.

After the formation of anhydrotetracycline, ATC [[monooxygenase]] (''OxyS'') [[oxidize]]s the C-6 position in an [[enantioselective]] manner in the presence of the [[Cofactor (biochemistry)|cofactor]] [[NADPH]] and [[atmospheric oxygen]] to produce 5a,11a-dehydrotetracycline.<ref>{{Cite journal |vauthors=Peric-Concha N, Borovicka B, Long PF, Hranueli D, Waterman PG, Hunter IS |date=November 2005 |title=Ablation of the otcC gene encoding a post-polyketide hydroxylase from the oxytetracyline biosynthetic pathway in Streptomyces rimosus results in novel polyketides with altered chain length |journal=The Journal of Biological Chemistry |volume=280 |issue=45 |pages=37455–37460 |doi=10.1074/jbc.M503191200 |pmid=16148009 |doi-access=free}}</ref> Next, a [[hydroxylation]] occurs at the C-5 position of 5a,11a-dehydrotetracycline via the [[oxygenase]] encoded as ''OxyE'' in the oxytetracycline gene cluster. This produces the intermediate 5a,11a-dehydro-oxytetracycline. However, the exact mechanism of this step remains unclear. The final step of this biosynthesis occurs through the [[Reduction (chemistry)|reduction]] of a [[double bond]] in the [[Enone|α, β—unsaturated ketone]] of 5a,11a-dehydro-oxytetracycline. In this final step, the cofactor NADPH is employed by ''TchA'' ([[reductase]]) as the [[reducing agent]]. Upon reduction, the [[enol]] form is favored due to [[Conjugated system|conjugation]], thus producing the aromatic polyketide oxytetracycline. Figure 2 shows the biosynthesis as described above, as well as an arrow-pushing mechanism of NADPH being used as the final cofactor in the biosynthesis of oxytetracycline.

[[File:Biosynthesis of Oxytetracycline.png|alt=|thumb|center|upright=4|Figure 2. Biosynthesis of oxytetracycline starting from the intermediate anhydrotetracycline. Bottom: Proposed arrow-pushing mechanism of oxytetracycline formation.]]

== Veterinary indications ==
Oxytetracycline is used to control the outbreak of [[Diseases of the honeybee|American foulbrood and European foulbrood]] in [[honeybee]]s.

Oxytetracycline can be used to correct breathing disorders in [[livestock]]. It is administered in a powder or through an intramuscular injection. American livestock producers apply oxytetracycline to livestock feed to prevent diseases and infections in cattle and poultry. The antibiotic is partially absorbed in the [[gastrointestinal tract]] of the animal and the remaining is deposited in manure. Researchers at the [[Agricultural Research Service]] studied the breakdown of oxytetracycline in manure depending on various environmental conditions. They found the breakdown slowed with increased saturation of the manure and concluded this was a result of decreased oxygen levels.<ref>{{Cite web |date=March 4, 2010 |title=Assessing Antibiotic Breakdown in Manure |url=https://www.ars.usda.gov/news-events/news/research-news/2010/assessing-antibiotic-breakdown-in-manure/ |access-date=5 February 2023 |publisher=Agricultural Research Service, U.S. Department of Agriculture |vauthors=Perry A}}</ref> This research helps producers understand the effects of oxytetracycline in animal feed on the environment, bacteria, and antimicrobial resistance.

Oxytetracycline is used to mark fish which are released and later recaptured. The oxytetracycline interferes with bone deposition, leaving a visible mark on growing bones.

Oxytetracycline has been formulated as a broad-spectrum [[anti-infective]] for fish under the name Terramycin 200 (TM200).<ref>{{Cite web |title=Terramycin 200 Antibiotic for Disease Control in Fish Farming |url=https://syndel.com/product/terramycin-200-for-fish-oxytetracycline/ |access-date=2019-12-12 |website=Syndel |language=en}}</ref> It is used to control certain diseases that adversely affect [[Aquaculture of salmonids|salmonids]], [[catfish]], and [[lobster]]s.

== References ==
{{Reflist}}

{{Antibiotics and chemotherapeutics for dermatological use}}
{{Gynecological anti-infectives and antiseptics}}
{{TetracyclineAntiBiotics}}

[[Category:Tetracycline antibiotics]]
[[Category:Western honey bee medications]]
[[Category:Drugs developed by Pfizer]]
[[Category:Dimethylamino compounds]]