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Publication Abstract from PubMed

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 (Ki* of 0.65 +/- 0.05 muM). 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.

Inhibiting the beta-Lactamase of Mycobacterium tuberculosis (Mtb) with Novel Boronic Acid Transition-State Inhibitors (BATSIs).,Kurz SG, Hazra S, Bethel CR, Romagnoli C, Caselli E, Prati F, Blanchard JS, Bonomo RA ACS Infect Dis. 2015 Jun 12;1(6):234-42. doi: 10.1021/acsinfecdis.5b00003. Epub, 2015 Apr 15. PMID:27622739^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.