Inhibiting the β-Lactamase of Mycobacterium tuberculosis (Mtb) with Novel Boronic Acid Transition-State Inhibitors (BATSIs).
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.
Department of Medicine, Tufts Medical Center , 600 Washington Street, No. 257, Boston, Massachusetts 02111, United States.
Sebastian G
SG
Kurz
Department of Biotechnology, Indian Institute of Technology Roorkee (IITR) , Roorkee, Uttarakhand 247667, India.
Saugata
S
Hazra
Research Service, Louis Stokes Cleveland Veterans Affairs Medical Center, 10701 East Boulevard, Cleveland, Ohio 44106, United States.
Christopher R
CR
Bethel
Department of Life Science, University of Modena and Reggio Emilia , Via Campi 183, 41100 Modena, Italy.
Chiara
C
Romagnoli
Department of Life Science, University of Modena and Reggio Emilia , Via Campi 183, 41100 Modena, Italy.
Emilia
E
Caselli
Department of Life Science, University of Modena and Reggio Emilia , Via Campi 183, 41100 Modena, Italy.
Fabio
F
Prati
Department of Biochemistry, Albert Einstein College of Medicine , 1300 Morris Park Avenue, Bronx, New York 10461, United States.
John S
JS
Blanchard
Research Service, Louis Stokes Cleveland Veterans Affairs Medical Center, 10701 East Boulevard, Cleveland, Ohio 44106, United States.
Robert A
RA
Bonomo
Mycobacterium tuberculosis; acylation high-energy intermediate; boronic acid transitional-state inhibitors; cefoperazone analogue EC19; deacylation high-energy intermediate; β-lactamase inhibition