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

Sebastian G. Kurz, Saugata Hazra, Christopher R. Bethel, Chiara Romagnoli, Emilia Caselli, Fabio Prati, John S. Blanchard, Robert A. Bonomo

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)234-242
Number of pages9
JournalACS Infectious Diseases
Volume1
Issue number6
DOIs
StatePublished - Jan 8 2016

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Boronic Acids
Mycobacterium tuberculosis
Cefoperazone
Clavulanic Acid
Enzymes
Therapeutics

Keywords

  • acylation high-energy intermediate
  • boronic acid transitional-state inhibitors
  • cefoperazone analogue EC19
  • deacylation high-energy intermediate
  • Mycobacterium tuberculosis
  • β-lactamase inhibition

ASJC Scopus subject areas

  • Infectious Diseases

Cite this

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, Vol. 1, No. 6, 08.01.2016, p. 234-242.

Research output: Contribution to journalArticle

Kurz, Sebastian G. ; Hazra, Saugata ; Bethel, Christopher R. ; Romagnoli, Chiara ; Caselli, Emilia ; Prati, Fabio ; Blanchard, John S. ; Bonomo, Robert A. / Inhibiting the β-Lactamase of Mycobacterium tuberculosis (Mtb) with Novel Boronic Acid Transition-State Inhibitors (BATSIs). In: ACS Infectious Diseases. 2016 ; Vol. 1, No. 6. pp. 234-242.
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