Product Code Database
Clavulanic acid 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 Beta-lactamase, which otherwise inactivates most penicillins.
In its most common preparations, potassium clavulanate (clavulanic acid as a salt of potassium) is combined with:
Clavulanic acid was patented in 1974. In addition to its β-lactamase inhibition, clavulanic acid shows off-target activity in the nervous system by upregulating the glutamate transporter 1 (GLT-1) and has been studied in the potential treatment of a variety of central nervous system disorders.
The United Kingdom 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.
Allergic reactions have been reported.
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. 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.
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 Beta-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 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.
In relation to its central nervous system actions, clavulanic acid has been studied preclinically in animal model of anxiety, sexual behavior, addiction, neuropathic pain, inflammation, epilepsy, Parkinson's disease, dementia, and stroke. In animals, including in rodents and/or monkeys, clavulanic acid has shown anxiolytic-like, antidepressant-like, aphrodisiac, nootropic, analgesic, antiaddictive, pro-dopaminergic, oxytocin, and neuroprotective effects. The drug has been studied clinically in humans in the treatment of erectile dysfunction, depression, substance dependence, and pain, with positive or mixed preliminary results for these conditions reported.
Clavulanic acid was under formal development by Revaax Pharmaceuticals (now Ocuphire Pharma) for the treatment of erectile dysfunction, , major depressive disorder, neurodegenerative disorders, and Parkinson's disease. However, development for these indications was discontinued by 2014. The developmental code name of clavulanic acid was RX-10100 and its tentative brand names were Serdaxin and Zoraxel. Although its development was discontinued, interest in clavulanic acid for potential nervous system-related uses has continued as of 2024.
|
|
