Inhibiting the β-Lactamase of Mycobacterium tuberculosis (Mtb) with Novel Boronic Acid Transition-State Inhibitors (BATSIs)

BlaC, the single chromosomally encoded beta-lactamase of Mycobacterium tuberculosis, has been identified as a promising target for novel therapies that rely upon beta-lactamase inhibition. Boronic acid transition state inhibitors (BATSIs) are a class of beta-lactamase inhibitors which permit rational inhibitor design by combinations of various R1 and R2 side chains. To explore the structural determinants of effective inhibition, we screened a panel of 25 BATSIs to explore key structure function relationships. We identified a cefoperazone analogue, EC19, which displayed slow, time dependent inhibition against BlaC with a potency similar to that of clavulanate (K-i* of 0.65 +/- 0.05 mu M). To further characterize the molecular basis of inhibition, we solved the crystallographic structure of the EC19-BlaC(N172A) complex and expanded our analysis to variant enzymes. The results of this structure function analysis encourage the design of a novel class of beta-lactamase inhibitors, BATSIs, to be used against Mycobacterium tuberculosis.