Download MendeleyInhibiting the beta-Lactamase of Mycobacterium tuberculosis (Mtb) with Novel Boronic Acid Transition-State Inhibitors (BATSIs).
Kurz, S.G., Hazra, S., Bethel, C.R., Romagnoli, C., Caselli, E., Prati, F., Blanchard, J.S., Bonomo, R.A.(2015) ACS Infect Dis 1: 234-242
- PubMed: 27622739
- DOI: https://doi.org/10.1021/acsinfecdis.5b00003
- Primary Citation of Related Structures:
4X6T - PubMed Abstract:
BlaC, the single chromosomally encoded β-lactamase of Mycobacterium tuberculosis, has been identified as a promising target for novel therapies that rely upon β-lactamase inhibition. Boronic acid transition-state inhibitors (BATSIs) are a class of β-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 (Ki* of 0.65 ± 0.05 μM). 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 β-lactamase inhibitors, BATSIs, to be used against Mycobacterium tuberculosis.
Organizational Affiliation:
Department of Medicine, Tufts Medical Center , 600 Washington Street, No. 257, Boston, Massachusetts 02111, United States.
