Clavulanic acid
Encyclopedia
Clavulanic acid (icon) is a competitive
β-lactamase inhibitor
(marketed by GlaxoSmithKline
, formerly Beecham
) combined with penicillin
group antibiotic
s to overcome certain types of antibiotic resistance
. It is used to overcome 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, Synulox[ veterinary] , and others) or ticarcillin
.
The substance is also under investigation as a NAALADase inhibitor with purported antidepressant and aphrodisiac properties. Clinical trials are underway on XR ("Serdaxin") and IR ("RX-10100", "Zoraxel") formulations by Rexahn in the US, although the Phase II results are not encouraging.
Clavulanic acid is an example of a clavam
.
, which produces clavulanic acid.
Clavulanic acid is biosynthetically generated from the amino acid arginine
and the sugar glyceraldehyde 3-phosphate
.
. 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.
s. 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.
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.
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.
Competitive inhibition
Competitive inhibition is a form of enzyme inhibition where binding of the inhibitor to the active site on the enzyme prevents binding of the substrate and vice versa.-Mechanism:...
β-lactamase inhibitor
Beta-lactamase inhibitor
A beta-lactamase inhibitor is a drug given in conjunction with a beta-lactam antibiotic. Although the inhibitor does not usually have significant antibiotic activity on its own, it inhibits activity of beta-lactamase, a protein that confers resistance of beta-lactam antibiotics to...
(marketed by GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
, formerly Beecham
Beecham (pharmaceutical company)
Beecham was a British pharmaceutical company. It was once a constituent of the FTSE 100 Index. Beecham, after having merged with SmithKline Beckman, merged with GlaxoWellcome to become GlaxoSmithKline .-History:...
) combined with penicillin
Penicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
group antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s to overcome certain types of antibiotic resistance
Antibiotic resistance
Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...
. It is used to overcome resistance in bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
that secrete β-lactamase
Beta-lactamase
Beta-lactamases are enzymes produced by some bacteria and are responsible for their resistance to beta-lactam antibiotics like penicillins, cephamycins, and carbapenems . These antibiotics have a common element in their molecular structure: a four-atom ring known as a beta-lactam...
, which otherwise inactivates most penicillins. In its most common form, the potassium salt potassium clavulanate is combined with amoxicillin
Amoxicillin
Amoxicillin , formerly amoxycillin , and abbreviated amox, is a moderate-spectrum, bacteriolytic, β-lactam antibiotic used to treat bacterial infections caused by susceptible microorganisms. It is usually the drug of choice within the class because it is better absorbed, following oral...
(co-amoxiclav
Co-amoxiclav
Amoxicillin/clavulanic acid or co-amoxiclav is a combination antibiotic consisting of amoxicillin trihydrate, a β-lactam antibiotic, and potassium clavulanate, a β-lactamase inhibitor...
, trade names Augmentin, Synulox
Ticarcillin
Ticarcillin is a carboxypenicillin. It is almost invariably sold and used in combination with clavulanate as Timentin. Because it is a penicillin, it also falls within the larger class of beta-lactam antibiotics. Its main clinical use is as an injectable antibiotic for the treatment of...
.
The substance is also under investigation as a NAALADase inhibitor with purported antidepressant and aphrodisiac properties. Clinical trials are underway on XR ("Serdaxin") and IR ("RX-10100", "Zoraxel") formulations by Rexahn in the US, although the Phase II results are not encouraging.
Clavulanic acid is an example of a clavam
Clavam
A clavam is a molecule similar to a penam, but with an oxygen substituted for the sulfur. Thus, they are also known as oxapenams.An example is clavulanic acid....
.
Source
The name is derived from the Streptomyces clavuligerusStreptomyces clavuligerus
Streptomyces clavuligerus is a species of Gram-positive bacterium that produces clavulanic acid.S. clavuligerus ATCC 27064 was first described by Higgens and Kastner, who isolated it from a South American soil sample...
, which produces clavulanic acid.
Clavulanic acid is biosynthetically generated from the amino acid arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
and the sugar glyceraldehyde 3-phosphate
Glyceraldehyde 3-phosphate
Glyceraldehyde 3-phosphate, also known as triose phosphate or 3-phosphoglyceraldehyde and abbreviated as G3P, GADP, GAP, TP, GALP or PGAL, is a chemical compound that occurs as an intermediate in several central metabolic pathways of all organisms...
.
History
Clavulanic acid was discovered around 1974/75 by British scientists working at the drug company BeechamBeecham (pharmaceutical company)
Beecham was a British pharmaceutical company. It was once a constituent of the FTSE 100 Index. Beecham, after having merged with SmithKline Beckman, merged with GlaxoWellcome to become GlaxoSmithKline .-History:...
. 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 antibioticBeta-lactam antibiotic
β-Lactam antibiotics are a broad class of antibiotics, consisting of all antibiotic agents that contains a β-lactam nucleus in its molecular structure. This includes penicillin derivatives , cephalosporins , monobactams, and carbapenems...
s. However, the similarity in chemical structure allows the molecule to interact with the enzyme β-lactamase
Beta-lactamase
Beta-lactamases are enzymes produced by some bacteria and are responsible for their resistance to beta-lactam antibiotics like penicillins, cephamycins, and carbapenems . These antibiotics have a common element in their molecular structure: a four-atom ring known as a beta-lactam...
secreted by certain bacteria to confer resistance to β-lactam antibiotics. Clavulanic acid is a suicide inhibitor, covalently bonding to a serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
residue in the active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
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 jaundiceCholestasis
In medicine, cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system such as can occur from a gallstone or malignancy and metabolic types of...
and acute hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
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.
The UK
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
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
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
has been reported.