Cyclic boronates as versatile scaffolds for KPC-2 β-lactamase inhibition

  • RSC Med Chem. 2020 Jan 10;11(4):491-496. doi: 10.1039/c9md00557a.
Catherine L Tooke  1  2 ,  Philip Hinchliffe  1 ,  Alen Krajnc  3 ,  Adrian J Mulholland  2 ,  Jürgen Brem  3 ,  Christopher J Schofield  3 ,  James Spencer  1
Affiliations
  • 1. School of Cellular and Molecular Medicine , Biomedical Sciences Building , University of Bristol , Bristol , BS8 1TD , UK . Email: [email protected].
  • 2. Centre for Computational Chemistry , School of Chemistry , University of Bristol , Bristol , BS8 1TS , UK.
  • 3. Chemistry Research Laboratory , Department of Chemistry , University of Oxford , 12 Mansfield Road , Oxford , OX1 3TA , UK.
PMID: 33479650 DOI: 10.1039/c9md00557a
Abstract

Klebsiella pneumoniae carbapenemase-2 (KPC-2) is a serine-β-lactamase (SBL) capable of hydrolysing almost all β-lactam Antibiotics. We compare KPC-2 inhibition by vaborbactam, a clinically-approved monocyclic boronate, and VNRX-5133 (taniborbactam), a bicyclic boronate in late-stage clinical development. Vaborbactam inhibition is slowly reversible, whereas taniborbactam has an off-rate indicating essentially irreversible complex formation and a 15-fold higher on-rate, although both potentiate β-lactam activity against KPC-2-expressing K. pneumoniae. High resolution X-ray crystal structures reveal closely related binding modes for both inhibitors to KPC-2, with differences apparent only in positioning of the endocyclic boronate ester oxygen. The results indicate the bicyclic boronate scaffold as both an efficient, long-lasting, KPC-2 inhibitor and capable of supporting further iterations that may improve potency against specific enzyme targets and pre-empt the emergence of inhibitor resistant KPC-2 variants.

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