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 synthesized to explore key structure-function relationships. We identified a cefoperazone analogue, EC19, which displayed slow, tight-binding inhibition against BlaC. To further characterize the molecular basis of inhibition, we solved the three-dimensional structure of the EC19-BlaC 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.

Inhibiting the β-Lactamase of Mycobacterium tuberculosis (Mtb) with Novel Boronic Acid Transition-State Inhibitors (BATSIs) / Kurz, Sebastian G.; Hazra, Saugata; Bethel, Christopher R.; Romagnoli, Chiara; Caselli, Emilia; Prati, Fabio; Blanchard, John S.; Bonomo, Robert A.. - In: ACS INFECTIOUS DISEASES. - ISSN 2373-8227. - STAMPA. - 1:6(2015), pp. 234-242. [10.1021/acsinfecdis.5b00003]

Inhibiting the β-Lactamase of Mycobacterium tuberculosis (Mtb) with Novel Boronic Acid Transition-State Inhibitors (BATSIs)

ROMAGNOLI, Chiara;CASELLI, Emilia;PRATI, Fabio;
2015

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 synthesized to explore key structure-function relationships. We identified a cefoperazone analogue, EC19, which displayed slow, tight-binding inhibition against BlaC. To further characterize the molecular basis of inhibition, we solved the three-dimensional structure of the EC19-BlaC 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.
2015
15-apr-2015
1
6
234
242
Inhibiting the β-Lactamase of Mycobacterium tuberculosis (Mtb) with Novel Boronic Acid Transition-State Inhibitors (BATSIs) / Kurz, Sebastian G.; Hazra, Saugata; Bethel, Christopher R.; Romagnoli, Chiara; Caselli, Emilia; Prati, Fabio; Blanchard, John S.; Bonomo, Robert A.. - In: ACS INFECTIOUS DISEASES. - ISSN 2373-8227. - STAMPA. - 1:6(2015), pp. 234-242. [10.1021/acsinfecdis.5b00003]
Kurz, Sebastian G.; Hazra, Saugata; Bethel, Christopher R.; Romagnoli, Chiara; Caselli, Emilia; Prati, Fabio; Blanchard, John S.; Bonomo, Robert A....espandi
File in questo prodotto:
File Dimensione Formato  
Kurz et al_acsinfecdis 2015_just_accepted.pdf

Open access

Tipologia: Versione dell'autore revisionata e accettata per la pubblicazione
Dimensione 1.02 MB
Formato Adobe PDF
1.02 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1070086
Citazioni
  • ???jsp.display-item.citation.pmc??? 12
  • Scopus 27
  • ???jsp.display-item.citation.isi??? 27
social impact