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Clavulanic Acid

Clavulanic acid is a beta-lactamase inhibitor (marketed by GlaxoSmithKline, formerly Beecham) sometimes 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 [brand name Augmentin] or the veterinary formulation Synulox from Pfizer, or [Clavulox]) or ticarcillin. It is also under investigation as a NAALADase inhibitor with possible antidepressant properties, as in page 15 of this patent. Clinical trials are underway on XR ("Serdaxin") and IR ("RX-10100") formulations by Rexahn in the US.

Clavulanic Acid


Fig: clavulanic acid

ptr Source:

The name is derived from the Streptomyces clavuligerus, which produces clavulanic acid.

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

Clavulanic Acid Mode of Action and Biosynthesis

β-Lactamases, which catalyse hydrolysis of the β-lactam ring, are amongst the most important mediators of antibiotic resistance and some β-lactams, including clavulanic acid, were explicitly developed as β-lactamase antagonists. Clavulanic acid inhibits Class A β-Lactamases by reacting to form acyl-enzyme complexes that are stable with respect to hydrolysis, a process closely related to the mode of action of β-lactam antibiotics such as the penicillins that inhibit transpeptidases involved in cell wall biosynthesis.

Although clavulanic acid is a small molecule (C8H8NO5) and contains only two chiral centres it is thermodynamically unstable and it has not been made via asymmetric total synthesis. We are investigating the biosynthetic pathway to clavulanic acid - our work involves structural work, functional analyses, and mechanistic studies. Techniques involved in this research include molecular biology, X-ray crystallography kinetics and organic synthesis. The latter is important since the late stage intermediates in the pathway are difficult to prepare and unstable. Studies on the multistep pathway (in collaboration with Inger Andersson and Janos Hajdu) have led to surprises including the trifunctional role of a single oxygenase and the fact that it proceeds via intermediates that are almost enantiomers of the final product.

Clavulanic Acid Mode

Although clavulanic acid is a small molecule (C8H8NO5) and contains only two chiral centres it is thermodynamically unstable and it has not been made via asymmetric total synthesis. We are investigating the biosynthetic pathway to clavulanic acid - our work involves structural work, functional analyses, and mechanistic studies. Techniques involved in this research include molecular biology, X-ray crystallography kinetics and organic synthesis. The latter is important since the late stage intermediates in the pathway are difficult to prepare and unstable. Studies on the multistep pathway (in collaboration with Inger Andersson and Janos Hajdu) have led to surprises including the trifunctional role of a single oxygenase and the fact that it proceeds via intermediates that are almost enantiomers of the final product.

Clavulanic Acid Mode
ptr 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, particularly in men and those aged over 65 years. 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 should 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.