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

Catherine L Tooke, Philip Hinchliffe, Alec Kranjnc, Adrian J Mulholland, Jürgen Brem, Christopher J Schofield, James Spencer*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

132 Downloads (Pure)


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.
Original languageEnglish
Pages (from-to)491-496
Number of pages6
JournalRSC medicinal chemistry
Issue number4
Publication statusPublished - 10 Jan 2020

Bibliographical note

This journal is © The Royal Society of Chemistry 2020.


Dive into the research topics of 'Cyclic boronates as versatile scaffolds for KPC-2 β-lactamase inhibition'. Together they form a unique fingerprint.
  • HPC (High Performance Computing) Facility

    Susan L Pywell (Manager), Simon A Burbidge (Other), Polly E Eccleston (Other) & Simon H Atack (Other)

    Facility/equipment: Facility

Cite this