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 β-lactamase, which otherwise inactivates most penicillins. In its most common preparations, potassium clavulanate (clavulanic acid as a salt of potassium) is combined with: amoxicillin (co-amoxiclav, trade names Augmentin, Tyclav, Clavamox (veterinary), Synulox (veterinary), and others) ticarcillin (co-ticarclav, 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. This is, in part, because of its efficacy against gram-negative bacteria 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 during therapy or shortly after. 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. Allergic reactions have been reported. Sources The name is derived from strains of Streptomyces clavuligerus, which produces clavulanic acid. Biosynthesis The β-lactam 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, using glyceraldehyde-3-phosphate 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, β-lactam synthetase, and N2-(2-carboxyethyl)-L-arginine (CEA) synthase. Clavaminate synthase is a non-heme oxygenase dependent on iron and α-keto-glutarate and 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-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 –