Clavulanic acid is a
β-lactam drug that functions as a
mechanism-based β-lactamase inhibitor
Beta-lactamases, (β-lactamases) are enzymes () produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, monobactams and carbapenems ( ertapenem), although carbapene ...
. While not effective by itself as an
antibiotic, when combined with
penicillin-group antibiotics, it can overcome
antibiotic resistance in
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...
that secrete
β-lactamase
Beta-lactamases, (β-lactamases) are enzymes () produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, monobactams and carbapenems ( ertapenem), although carbapenems ...
, which otherwise inactivates most penicillins.
In its most common preparations, potassium clavulanate (clavulanic acid as a salt of potassium) is combined with:
*
amoxicillin
Amoxicillin is an antibiotic medication used to treat a number of bacterial infections. These include middle ear infection, strep throat, pneumonia, skin infections, and urinary tract infections among others. It is taken by mouth, or less c ...
(
co-amoxiclav, trade names Augmentin, Tyclav, Clavamox (
veterinary
Veterinary medicine is the branch of medicine that deals with the prevention, management, diagnosis, and treatment of disease, disorder, and injury in animals. Along with this, it deals with animal rearing, husbandry, breeding, research on nutri ...
), Synulox (
veterinary
Veterinary medicine is the branch of medicine that deals with the prevention, management, diagnosis, and treatment of disease, disorder, and injury in animals. Along with this, it deals with animal rearing, husbandry, breeding, research on nutri ...
), and others)
*
ticarcillin
Ticarcillin is a carboxypenicillin. It can be sold and used in combination with clavulanate as ticarcillin/clavulanic acid. Because it is a penicillin, it also falls within the larger class of beta-lactam antibiotics. Its main clinical use is as ...
(
co-ticarclav
Ticarcillin/clavulanic acid, or co-ticarclav, is a combination antibiotic consisting of ticarcillin, a Β-Lactam antibiotic, β-lactam antibiotic, and clavulanic acid, a Β-Lactamase inhibitor, β-lactamase inhibitor. This combination results in ...
, trade name Timentin)
Clavulanic acid was patented in 1974.
Medical uses
Amoxicillin-clavulanic acid is a first-line treatment for many types of infections, including sinus infections, and urinary tract infections, including
pyelonephritis
Pyelonephritis is inflammation of the kidney, typically due to a bacterial infection. Symptoms most often include fever and flank tenderness. Other symptoms may include nausea, burning with urination, and frequent urination. Complications may ...
. This is, in part, because of its efficacy against
gram-negative bacteria
Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...
which tend to be more difficult to control than
gram-positive bacteria with chemotherapeutic antibiotics.
Adverse effects
The use of clavulanic acid with penicillins has been associated with an increased incidence of
cholestatic jaundice and acute
hepatitis
Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes ( jaundice), poor appetite, vomiting, tiredness, abdominal ...
during therapy or shortly after. The associated jaundice is usually self-limiting and very rarely fatal.
The
UK Committee on Safety of Medicines
The Committee on Safety of Medicines (CSM) was an independent advisory committee that advised the UK Licensing Authority on the quality, efficacy, and safety of medicines.
Following the thalidomide tragedy of 1957 to 1961, in 1963 the government ...
(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.
Allergic reactions
Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derm ...
have been reported.
Sources
The name is derived from strains of ''
Streptomyces clavuligerus
''Streptomyces clavuligerus'' is a species of Gram-positive bacterium notable for producing clavulanic acid.
''S. clavuligerus'' ATCC 27064 (NRRL 3585, DSM 738) was first described by Higgens and Kastner (1971), who isolated it from a South Am ...
'', which produces clavulanic acid.
Biosynthesis
The
β-lactam
A beta-lactam (β-lactam) ring is a four-membered lactam. A ''lactam'' is a cyclic amide, and ''beta''-lactams are named so because the nitrogen atom is attached to the β-carbon atom relative to the carbonyl. The simplest β-lactam possible is ...
like structure of clavulanic acid looks structurally similar to
penicillin, but the biosynthesis of this molecule involves a different biochemical pathway. Clavulanic acid is produced by the bacterium ''
Streptomyces clavuligerus
''Streptomyces clavuligerus'' is a species of Gram-positive bacterium notable for producing clavulanic acid.
''S. clavuligerus'' ATCC 27064 (NRRL 3585, DSM 738) was first described by Higgens and Kastner (1971), who isolated it from a South Am ...
'', using
glyceraldehyde-3-phosphate
Glyceraldehyde 3-phosphate, also known as triose phosphate or 3-phosphoglyceraldehyde and abbreviated as G3P, GA3P, GADP, GAP, TP, GALP or PGAL, is a metabolite that occurs as an intermediate in several central pathways of all organisms.Nelson, ...
and
L-arginine as starting materials.
Although each of the intermediates of the pathway are known, the exact mechanism for all of the enzymatic reactions are not fully understood. The process mainly involves 3 enzymes:
clavaminate synthase
Clavaminate synthase (, ''clavaminate synthase 2'', ''clavaminic acid synthase'') is an enzyme with systematic name ''deoxyamidinoproclavaminate,2-oxoglutarate:oxygen oxidoreductase (3-hydroxylating)''. This enzyme catalyses the following chemical ...
, β-lactam synthetase, and
N2-(2-carboxyethyl)-L-arginine (CEA)
synthase.
Clavaminate synthase
Clavaminate synthase (, ''clavaminate synthase 2'', ''clavaminic acid synthase'') is an enzyme with systematic name ''deoxyamidinoproclavaminate,2-oxoglutarate:oxygen oxidoreductase (3-hydroxylating)''. This enzyme catalyses the following chemical ...
is a non-heme oxygenase dependent on iron and
α-keto-glutarate and is encoded by orf5 of the clavulanic acid
gene cluster
A gene family is a set of homologous genes within one organism. A gene cluster is a group of two or more genes found within an organism's DNA that encode similar polypeptides, or proteins, which collectively share a generalized function and are ...
. 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-containing reaction center, yet do not occur in sequence and affect different areas of the clavulanic acid structure.
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
A beta-lactam (β-lactam) ring is a four-membered lactam. A ''lactam'' is a cyclic amide, and ''beta''-lactams are named so because the nitrogen atom is attached to the β-carbon atom relative to the carbonyl. The simplest β-lactam possible is ...
is not proven, but is believed to occur in coordination with a CEA synthase and
ATP.
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
Glyceraldehyde 3-phosphate, also known as triose phosphate or 3-phosphoglyceraldehyde and abbreviated as G3P, GA3P, GADP, GAP, TP, GALP or PGAL, is a metabolite that occurs as an intermediate in several central pathways of all organisms.Nelson, ...
with
L-arginine
Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the a ...
in the presence of thiamine diphosphate (TDP or
thiamine pyrophosphate
Thiamine pyrophosphate (TPP or ThPP), or thiamine diphosphate (ThDP), or cocarboxylase is a thiamine (vitamin B1) derivative which is produced by the enzyme thiamine diphosphokinase. Thiamine pyrophosphate is a cofactor that is present in all liv ...
), which is the first step of the clavulanic acid biosynthesis.
History
Clavulanic acid was discovered around 1974-75 by British scientists working at the drug company
Beecham from the bacteria ''Streptomyces clavuligerus''.
After several attempts, Beecham finally filed for
US patent
Under United States law, a patent is a right granted to the inventor of a (1) process, machine, article of manufacture, or composition of matter, (2) that is new, useful, and non-obvious. A patent is the right to exclude others, for a limited ...
protection for the drug in 1981, and U.S. Patents 4,525,352, 4,529,720, and 4,560,552 were granted in 1985.
Clavulanic acid has negligible intrinsic antimicrobial activity, despite sharing the β-lactam ring that is characteristic of
β-lactam antibiotic
β-lactam antibiotics (beta-lactam antibiotics) are antibiotics that contain a beta-lactam ring in their chemical
structure. This includes penicillin derivatives (penams), cephalosporins and cephamycins (cephems), monobactams, carbapenems and ...
s. However, the similarity in chemical structure allows the molecule to interact with the enzyme
β-lactamase
Beta-lactamases, (β-lactamases) are enzymes () produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, monobactams and carbapenems ( ertapenem), although carbapenems ...
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 attacks 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.
References
{{DEFAULTSORT:Clavulanic Acid
Beta-lactamase inhibitors