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Profiling interactions of vaborbactam with metallo-β-lactamases

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Langley, Gareth W., Cain, Ricky, Tyrrell, Jonathan M., Hinchliffe, Philip, Calvopiña, Karina, Tooke, Catherine L., Widlake, Emma, Dowson, Christopher G., Spencer, James, Walsh, Timothy R., Schofield, Christopher J. and Brem, Jürgen (2019) Profiling interactions of vaborbactam with metallo-β-lactamases. Bioorganic & Medicinal Chemistry Letters, 29 (15). pp. 1981-1984. doi:10.1016/j.bmcl.2019.05.031

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Official URL: http://dx.doi.org/10.1016/j.bmcl.2019.05.031

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Abstract

β-Lactams are the most successful antibacterials, yet their use is threatened by resistance, importantly as caused by β-lactamases. β-Lactamases fall into two mechanistic groups: the serine β-lactamases that utilise a covalent acyl-enzyme mechanism and the metallo β-lactamases that utilise a zinc-bound water nucleophile. Achieving simultaneous inhibition of both β-lactamase classes remains a challenge in the field. Vaborbactam is a boronate-based inhibitor that reacts with serine-β-lactamases to form covalent complexes that mimic tetrahedral intermediates in catalysis. Vaborbactam has recently been approved for clinical use in combination with the carbapenem meropenem. Here we show that vaborbactam moderately inhibits metallo-β-lactamases from all 3 subclasses (B1, B2 and B3), with a potency of around 20–100 fold below that by which it inhibits its current clinical targets, the Class A serine β-lactamases. This result contrasts with recent investigations of bicyclic boronate inhibitors, which potently inhibit subclass B1 MBLs but which presently lack activity against B2 and B3 enzymes. These findings indicate that cyclic boronate scaffolds have the potential to inhibit the full range of β-lactamases and justify further work on the development of boronates as broad-spectrum β-lactamase inhibitors.

Item Type: Journal Article
Subjects: Q Science > QR Microbiology
R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Beta lactam antibiotics, Beta lactamases -- Inhibitors, Drug resistance in microorganisms
Journal or Publication Title: Bioorganic & Medicinal Chemistry Letters
Publisher: Pergamon-Elsevier Science Ltd.
ISSN: 0960-894X
Official Date: 17 May 2019
Dates:
DateEvent
17 May 2019Published
16 May 2019Accepted
Volume: 29
Number: 15
Page Range: pp. 1981-1984
DOI: 10.1016/j.bmcl.2019.05.031
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
UNSPECIFIEDWellcome Trusthttp://dx.doi.org/10.13039/100010269
UNSPECIFIEDCancer Research UKhttp://dx.doi.org/10.13039/501100000289
UNSPECIFIED[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/N002679/1[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
BB/S50676X/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/S50676X/[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
UNSPECIFIEDCenter for Innovative Medicine, Johns Hopkins Universityhttp://dx.doi.org/10.13039/100012306

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