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 - Funding Information:
Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers R01AI100560 and R01AI063517 (to R.A.B.) and NIH AI060899 (to J.S.B.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This study was supported in part by funds and/or facilities provided by the Cleveland Department of Veterans Affairs, Veterans Affairs Merit Review Program Award 1I01BX001974, and the Geriatric Research Education and Clinical Center VISN 10 (to R.A.B.). Parts of this study were presented in the form of an abstract (European Congress of Clinical Microbiology and Infectious Diseases, Milan 2011, American Thoracic Society, San Diego 2014).
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 -
