Computational study on decarboxylation mechanism of β-lactamases inhibitors: Clavulanate vs. sulbactam

The decarboxylation of clavulanate and sulbactam in inhibition of class A β-lactamases were studied by quantum chemical methods. It was found that both clavulanate and sulbactam undergo direct proton transfer from carboxyl to C3, which results in the cleavage of C–CO2 bond. However, the calculated energy barriers are too high for the mechanism to be operative. For clavulanate decarboxylation, there is another channel, viz. proton transfer from carboxyl to carbonyl oxygen, and it is found to be energetically favored over the former. These conclusions explain the corresponding experimental results.