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

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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Article information


Accepted
08 Jan 2020
First published
10 Jan 2020

RSC Med. Chem., 2020, Accepted Manuscript
Article type
Research Article

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

C. L. Tooke, P. Hinchliffe, A. KRAJNC, A. J. Mulholland, J. Brem, C. J. Schofield and J. Spencer, RSC Med. Chem., 2020, Accepted Manuscript , DOI: 10.1039/C9MD00557A

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