Clavulanic acid

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 cat.	B (USA) B1 (Aust)
Legal status	Schedule 4 (Aust)
Routes	oral, IV
Pharmacokinetic data
Bioavailability	"well absorbed"
Metabolism	hepatic (extensive)
Half-life	1 hour
Excretion	renal (30–40%)
Identifiers
CAS number	58001-44-8
ATC code	J01CR (combinations with penicillins)
PubChem	CID 5280980
DrugBank	APRD00049
ChemSpider	4444466 Y
UNII	23521W1S24 Y
KEGG	D07711 Y
ChEBI	CHEBI:48947 Y
ChEMBL	CHEMBL777 Y
Chemical data
Formula	C8H9NO5
Mol. mass	199.16
SMILES	eMolecules & PubChem
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 Y Key:HZZVJAQRINQKSD-PBFISZAISA-N Y
Y(what is this?)  [//en.wikipedia.org/w/index.php?title=Special:ComparePages&rev1=443529372 9372&page2=Clavulanic acid (verify)]

Clavulanic acid (rINN) ( /klævjuːˌlænɨk ˈæsɨd/) is a competitive beta-lactamase inhibitor (marketed by GlaxoSmithKline, formerly Beecham) combined with penicillin group antibiotics to overcome certain types of antibiotic resistance. It is used to overcome resistance in bacteria that secrete beta-lactamase, which otherwise inactivates most penicillins. In its most common form, the potassium salt potassium clavulanate is combined with amoxicillin (co-amoxiclav, trade names Augmentin, Synulox [veterinary], and others) or ticarcillin.

The substance is also under investigation as a NAALADase inhibitor with purported antidepressant and aphrodisiac properties.^[1] Clinical trials are underway on XR ("Serdaxin") and IR ("RX-10100", "Zoraxel") formulations by Rexahn in the US^[2], although the Phase II results are not encouraging.^[3]

Clavulanic acid is an example of a clavam.

Source

The name is derived from the Streptomyces clavuligerus, which produces clavulanic acid.^[4][5]

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

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 beta-lactam antibiotics. However, the similarity in chemical structure allows the molecule to interact with the enzyme beta-lactamase secreted by certain bacteria to confer resistance to beta-lactam antibiotics. Clavulanic acid is a suicide inhibitor, covalently bonding to a serine residue in the active site of the beta-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 beta-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, in particular, in men and those over the age of 65. The associated jaundice is usually self-limiting and very rarely fatal.^[6]

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.^[7]

References

1. ^ http://www.google.com/patents/pdf/Therapeutic_treatment_for_sexual_dysfunc.pdf?id=Lhl_AAAAEBAJ&output=pdf&sig=ACfU3U0ESWXC1lRCKxRbO4OD8h9FFa6LyQ
2. ^ http://clinicaltrials.gov/ct2/results?term=rx-10100
3. ^ http://pharmalive.com/News/index.cfm?articleid=811952 Rexahn Pharmaceuticals Announces Phase II Results for Serdaxin as Treatment for Major Depressive Disorder
4. ^ 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. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=16251194. 
5. ^ 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. http://aac.asm.org/cgi/pmidlookup?view=long&pmid=14982786. 
6. ^ Joint Formulary Committee. British National Formulary, 47th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2004.
7. ^ 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. http://www.elsevier.es/en/revistas/allergologia-et-immunopathologia-105/hypersensitivity-to-clavulanic-acid-in-children-13130586-research-letters-2008.