クラブラン酸カリウム

関: clavulanate、clavulanate potassium、clavulanic acid

WordNet

a light soft silver-white metallic element of the alkali metal group; oxidizes rapidly in air and reacts violently with water; is abundant in nature in combined forms occurring in sea water and in carnallite and kainite and sylvite (同)K, atomic number 19

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ポタシウム,カリウム(金属元素;化学記号はK)

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/05/17 14:56:31」(JST)

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Clavulanic acid (rINN) /ˌklævjuːˈlænɨk ˈæsɨd/ is a β-lactam drug that functions as a mechanism-based β-lactamase inhibitor. While not effective by itself as an antibiotic, when combined with penicillin-group antibiotics, it can overcome antibiotic resistance in bacteria that secrete β-lactamase, which otherwise inactivates most penicillins.

The drug is marketed by GlaxoSmithKline.

In its most common form, the potassium salt potassium clavulanate is combined with:

amoxicillin (co-amoxiclav, trade names Augmentin, Tyclav (Beximco), Synulox [veterinary], and others) or
ticarcillin (co-ticarclav, trade name Timentin).

Clavulanic acid is an example of a clavam.

Sources

The name is derived from the Streptomyces clavuligerus, which produces clavulanic acid.^[1]^[2]

Clavulanic acid is biosynthetically generated from the amino acid arginine and the sugar glyceraldehyde 3-phosphate.

Biosynthesis

The intermediates of the biosynthesis of Clavualnic Acid^[3]

With the β-lactam like structure, clavulanic acid looks structurally similar to penicillin, but the biosynthesis of this molecule involves a different pathway and set of enzymes. Clavulanic acid is biosynthesized by the bacterium Streptomyces clavuligerus, using glyceraldehyde-3-phosphate and L-arginine as the starting materials of the pathway.^[3]^[4] Although all of the intermediates of the pathway are known, the exact mechanism of each enzymatic reaction is not fully understood. The biosynthesis mainly involves 3 enzymes: clavaminate synthase, β-lactam synthetase and N²-(2-carboxyethyl)-L-arginine synthase(CEA).^[3] Clavaminate synthase is a non-heme iron α-keto-glutarate dependent oxygenase that is encoded by orf5 of the clavualnic acid gene cluster. The specific mechanism of how this enzyme works is not fully understood, but this enzyme regulates 3 steps in the overall synthesis of clavulanic acid. All 3 steps occur in the same region of the catalytic iron center, yet do not occur in-sequence and affect different areas of the clavulanic acid structure.^[5]

β-lactam synthetase is a 54.5 kDa protein that is encoded by orf3 of the clavulanic acid gene cluster, and shows similarity to asparagine synthase – Class B enzymes. The exact mechanism on how this enzyme works to synthesize the β-lactam is not proven, but is believed to occur in coordination with a CEA synthase and ATP.^[6]

Proposed mechanism of beta-lactam synthetase in the biosynthesis of clavulanic acid.^[3]

CEA synthase is a 60.9 kDA protein and is the first gene found in the clavulanic acid biosynthesis gene cluster, encoded by orf2 of the clavualnic acid gene cluster. The specific mechanism of how this enzyme works is still under investigation; however, it is known that this enzyme has the ability to couple together glyceraldehyde-3-phosphate with L-arginine in the presence of thiamine diphosphate (TDP or thiamine pyrophosphate), which is the first step of the clavulanic acid biosynthesis.^[7]

Proposed mechanism of CEA synthetase in the biosynthesis of clavulanic acid.^[3]

History

Clavulanic acid was discovered around 1974/75 by British scientists working at the drug company Beecham. After several attempts, Beecham finally filed for US patent protection for the drug in 1981, and U.S. Patents 4,525,352, 4,529,720, and 4,560,552 were granted in 1985.

Mechanism of action

Clavulanic acid has negligible intrinsic antimicrobial activity, despite sharing the β-lactam ring that is characteristic of β-Lactam antibiotics. However, the similarity in chemical structure allows the molecule to interact with the enzyme β-Lactamase secreted by certain bacteria to confer resistance to β-lactam antibiotics.

Clavulanic acid is a suicide inhibitor, covalently bonding to a serine residue in the active site of the β-Lactamase. This restructures the clavulanic acid molecule, creating a much more reactive species that is attacked by another amino acid in the active site, permanently inactivating it, and thus inactivating the enzyme.

This inhibition restores the antimicrobial activity of β-lactam antibiotics against lactamase-secreting resistant bacteria. Despite this, some bacterial strains that are resistant even to such combinations have emerged.

Adverse effects

The use of clavulanic acid with penicillins has been associated with an increased incidence of cholestatic jaundice and acute hepatitis during therapy or shortly after. The associated jaundice is usually self-limiting and very rarely fatal.^[8]^[9]

The UK Committee on Safety of Medicines (CSM) recommends that treatments such as amoxicillin/clavulanic acid preparations be reserved for bacterial infections likely to be caused by amoxicillin-resistant β-lactamase-producing strains, and that treatment should not normally exceed 14 days.

Allergy has been reported.^[10]

References

^ Arulanantham H, Kershaw NJ, Hewitson KS, Hughes CE, Thirkettle JE, Schofield CJ (January 2006). "ORF17 from the clavulanic acid biosynthesis gene cluster catalyzes the ATP-dependent formation of N-glycyl-clavaminic acid". J. Biol. Chem. 281 (1): 279–87. doi:10.1074/jbc.M507711200. PMID 16251194.
^ Tahlan K, Park HU, Wong A, Beatty PH, Jensen SE (March 2004). "Two sets of paralogous genes encode the enzymes involved in the early stages of clavulanic acid and clavam metabolite biosynthesis in Streptomyces clavuligerus". Antimicrob. Agents Chemother. 48 (3): 930–9. doi:10.1128/AAC.48.3.930-939.2004. PMC 353097. PMID 14982786.
^ ^a ^b ^c ^d ^e Townsend, CA (Oct 2002). "New reactions in clavulanic acid biosynthesis.". Current Opinion in Chemical Biology 6 (5): 583–9. doi:10.1016/S1367-5931(02)00392-7. PMID 12413541.
^ Reading, C.; Cole, M. (1 May 1977). "Clavulanic Acid: a Beta-Lactamase-Inhibiting Beta-Lactam from Streptomyces clavuligerus". Antimicrobial Agents and Chemotherapy 11 (5): 852–857. doi:10.1128/AAC.11.5.852.
^ Busby, RW; Townsend, CA (Jul 1996). "A single monomeric iron center in clavaminate synthase catalyzes three nonsuccessive oxidative transformations.". Bioorganic & Medicinal Chemistry 4 (7): 1059–64. doi:10.1016/0968-0896(96)00088-0. PMID 8831977.
^ Bachmann, BO; Townsend, CA (Sep 19, 2000). "Kinetic mechanism of the beta-lactam synthetase of Streptomyces clavuligerus.". Biochemistry 39 (37): 11187–93. doi:10.1021/bi000709i. PMID 10985764.
^ Khaleeli, Nusrat; Li, Rongfeng; Townsend, Craig A. "Origin of the β-Lactam Carbons in Clavulanic Acid from an Unusual Thiamine Pyrophosphate-Mediated Reaction". Journal of the American Chemical Society 121 (39): 9223–9224. doi:10.1021/ja9923134.
^ Joint Formulary Committee. British National Formulary, 47th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2004.
^ "Drug Record - Amoxicillin-Clavulanate". LiverTox - Clinical and Research Information on Drug-Induced Liver Injury. Retrieved April 24, 2013.
^ Tortajada Girbés M, Ferrer Franco A, Gracia Antequera M, Clement Paredes A, García Muñoz E, Tallón Guerola M (2008). "Hypersensitivity to clavulanic acid in children". Allergol Immunopathol (Madr) 36 (5): 308–10. doi:10.1016/S0301-0546(08)75228-5. PMID 19080805.

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English Journal

Prevalence of Salmonella spp. in Cane Toads (Bufo marinus) from Grenada, West Indies, and their Antimicrobial Susceptibility.

Drake M, Amadi V, Zieger U, Johnson R, Hariharan H.SourceSchool of Veterinary Medicine, St George's University, West Indies,Grenada Pathobiology Academic Program, School of Veterinary Medicine, St George's University, West Indies, Grenada Anatomy and Physiology Academic Program, School of Veterinary Medicine, St George's University, West Indies, Grenada Office International des Epizooties (OIE) Reference Laboratory for Salmonellosis, Laboratory for Foodborne Zoonoses, Public Health Agency of Canada, Guelph, ON, Canada.
Zoonoses and public health.Zoonoses Public Health.2013 Sep;60(6):437-41. doi: 10.1111/zph.12018. Epub 2012 Oct 5.
Cloacal swabs and caecal contents sampled from 58 cane toads (Bufo marinus) in St George's parish, Grenada, during a 7-month period in 2011 were examined by an enrichment and selective culture method for presence of Salmonella spp. Twenty-four (41%) toads were positive for Salmonella spp. of which e
PMID 23035820

A Novel Extended-Spectrum β-Lactamase, SGM-1, from an Environmental Isolate of Sphingobium sp.

Lamoureaux TL, Vakulenko V, Toth M, Frase H, Vakulenko SB.SourceDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
Antimicrobial agents and chemotherapy.Antimicrob Agents Chemother.2013 Aug;57(8):3783-8. doi: 10.1128/AAC.00808-13. Epub 2013 May 28.
SGM-1 is a novel class A β-lactamase from an environmental isolate of Sphingobium sp. containing all of the distinct amino acid motifs of class A β-lactamases. It shares 77 to 80% amino acid sequence identity with putative β-lactamases that are present on the chromosome of all Sphingobium species
PMID 23716045

Multidrug and Heavy Metal-Resistant Raoultella planticola Isolated from Surface Water.

Koc S, Kabatas B, Icgen B.SourceDepartment of Biology, Kırıkkale University, 71450, Kirikkale, Turkey.
Bulletin of environmental contamination and toxicology.Bull Environ Contam Toxicol.2013 Aug;91(2):177-83. doi: 10.1007/s00128-013-1031-6. Epub 2013 Jun 11.
A surface water isolate of Raoultella sp. having both multidrug- and multimetal-resistant ability was isolated and identified as Raoultella planticola. R. planticola displayed resistance to 15 drugs like ampicillin, amoxicillin/clavulanic acid, aztreonam, erythromycin, imipenem, oxacillin, pefloxaci
PMID 23754693

Japanese Journal

小児中耳炎患者を対象としたクラブラン酸カリウム・アモキシシリン配合剤(クラバモックス^【○!R】)小児用ドライシロップの有効性, 安全性の検討

杉田麟也,山中昇,工藤典代 [他],伊藤理恵,川合基司,大脇一郎,浅野哲,永田傳
The Japanese journal of antibiotics 60(4), 221-241, 2007-08-25
NAID 10019820481

[最新の抗菌薬XXXVII] Potassium clavulanate/Ticarcillin sodium

藤森一平
Jap. J. Antibiotics 44, 365-387, 1991
NAID 80005871631

Degradation Kinetics of Sodium Sulbactam in Aqueous Solutions

萩中淳,若居純子,安田博幸,宇野豊三,中川照眞
Chemical & pharmaceutical bulletin 33(6), 2461-2468, 1985-06-25
… The pH-rate profile showed that the maximum stability of sodium sulbactam occurred in the pH range of 3.0 to 7.0,and that sodium sulbactam is much more stable than potassium clavulanate over the whole range of pH examined. …
NAID 110003625685

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リンク元	「clavulanate potassium」「クラブラン酸カリウム」
拡張検索	「amoxicillin-potassium clavulanate combination」「ticarcillin sodium/potassium clavulanate mixture」
関連記事	「clavulanate」

「clavulanate potassium」

Clavulanic acid
Systematic (IUPAC) name
	(2R,5R,Z)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid
Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy; category	B (USA); B1 (Aust);
Legal status	Schedule 4 (Au) rx only;
Routes of; administration	oral, IV
Pharmacokinetic data
Bioavailability	"well absorbed"
Metabolism	hepatic (extensive)
Half-life	1 hour
Excretion	renal (30–40%)
Identifiers
CAS Registry Number	58001-44-8
ATC code	J01CR (combinations with penicillins)
PubChem	CID 5280980
DrugBank	DB00766
ChemSpider	4444466
UNII	23521W1S24
KEGG	D07711
ChEBI	CHEBI:48947
ChEMBL	CHEMBL777
Chemical data
Formula	C8H9NO5
Molecular mass	199.16 g/mol
	SMILES O=C2N1[C@H](C(/O[C@@H]1C2)=C/CO)C(=O)O;
	InChI InChI=1S/C8H9NO5/c10-2-1-4-7(8(12)13)9-5(11)3-6(9)14-4/h1,6-7,10H,2-3H2,(H,12,13)/b4-1-/t6-,7-/m1/s1 ; Key:HZZVJAQRINQKSD-PBFISZAISA-N ;
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