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 category	B (USA) B1 (Aust)
Routes of administration	oral, IV
Legal status
Legal status	Schedule 4 (Au) rx only
Pharmacokinetic data
Bioavailability	"well absorbed"
Metabolism	hepatic (extensive)
Biological half-life	1 hour
Excretion	renal (30–40%)
Identifiers
CAS Number	58001-44-8
ATC code	J01CR (WHO) (combinations with penicillins)
PubChem	CID 5280980
DrugBank	DB00766
ChemSpider	4444466
UNII	23521W1S24
KEGG	D07711
ChEBI	CHEBI:48947
ChEMBL	CHEMBL777
Chemical data
Formula	C8H9NO5
Molar 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
(verify)

Clavulanic acid (rINN) /ˌklævjuːˈlænᵻk ˈæsᵻd/ 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.

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 Clavulanic 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 clavulanic 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 clavulanic 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

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. Joint Formulary Committee. British National Formulary, 47th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2004.
9. "Drug Record - Amoxicillin-Clavulanate". LiverTox - Clinical and Research Information on Drug-Induced Liver Injury. Retrieved April 24, 2013.
10. 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.