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

Journal article

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.

Authors: Tooke, C; Hinchliffe, P; Krajnc, A; Mulholland, A; Brem, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Royal Society of Chemistry
• Journal: RSC Medicinal Chemistry
• Volume: 11
• Issue: 4
• Pages: 491-496
• Publication date: 2020-01-10
• Acceptance date: 2020-01-08
• DOI: 10.1039/C9MD00557A
• Language: English
• Keywords: FFR