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

14 Scopus citations

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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Keywords

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

ASJC Scopus subject areas

  • Infectious Diseases

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