TY - JOUR
T1 - Inhibiting the β-Lactamase of Mycobacterium tuberculosis (Mtb) with Novel Boronic Acid Transition-State Inhibitors (BATSIs)
AU - Kurz, Sebastian G.
AU - Hazra, Saugata
AU - Bethel, Christopher R.
AU - Romagnoli, Chiara
AU - Caselli, Emilia
AU - Prati, Fabio
AU - Blanchard, John S.
AU - Bonomo, Robert A.
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2016/1/8
Y1 - 2016/1/8
N2 - 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.
AB - 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.
KW - Mycobacterium tuberculosis
KW - acylation high-energy intermediate
KW - boronic acid transitional-state inhibitors
KW - cefoperazone analogue EC19
KW - deacylation high-energy intermediate
KW - β-lactamase inhibition
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U2 - 10.1021/acsinfecdis.5b00003
DO - 10.1021/acsinfecdis.5b00003
M3 - Article
AN - SCOPUS:84967175816
SN - 2373-8227
VL - 1
SP - 234
EP - 242
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 6
ER -