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.
Fig: clavulanic acid
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.
