Download MendeleyCyclic boronates as versatile scaffolds for KPC-2 beta-lactamase inhibition.
Tooke, C.L., Hinchliffe, P., Krajnc, A., Mulholland, A.J., Brem, J., Schofield, C.J., Spencer, J.(2020) RSC Med Chem 11: 491-496
- PubMed: 33479650
- DOI: https://doi.org/10.1039/c9md00557a
- Primary Citation of Related Structures:
6TD0, 6TD1 - PubMed 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.
Organizational Affiliation:
School of Cellular and Molecular Medicine , Biomedical Sciences Building , University of Bristol , Bristol , BS8 1TD , UK . Email: [email protected].
