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Bicyclic Boronate β-Lactamase Inhibitors

Boronate containing compounds have potential for broad spectrum inhibition of β-lactamases. Recent studies have revealed bicyclic boronates as being of particular promise, including with respect to inhibiting both nucleophilic serine-β-lactamases (SBLs) and metallo-β-lactamases (MBLs).1-4 We have developed novel synthetic route to VNRX-5133 and investigated its spectrum of activity.5 VNRX-5133 (taniborbactam) is in Phase 3 clinical trials.6 VNRX-5133 manifests submicromolar IC50 values (0.53 – 0.008 μM) for representatives of all major classes of clinically-relevant β-lactamases tested; it is potent against some B1 subclass MBLs, e.g., widely-spread Verona-integron-encoded MBL, VIM-2 (IC50 ~ 0.5 nM). VNRX-5133 is substantially more potent against MBLs than clinically-approved monocyclic boronate SBL inhibitor Vaborbactam7. Biophysical analyses including crystal structures validate the proposed transition state analogue binding mode for VNRX-5133 and other bicyclic boronates with SBLs and MBLs. Unexpectedly, VNRX-5133 was observed in both bicyclic and tricyclic forms when bound to New Delhi metallo-β-lactamase, NDM-1.5 Although the relevance in solution of the crystallographically-observed forms is to be validated, this observation highlights the ability of boronate-based inhibitors to interchange between different binding modes/hybridization states when bound to proteins.


1. Krajnc, A. et al. Will morphing boron-based inhibitors beat the β-lactamases? Curr Opin Chem Biol 2019, 50, 101-110.
2. Brem, J. et al. Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates. Nat Commun 2016, 7, 12406.
3. Cahill, S. T. et al. Cyclic Boronates Inhibit All Classes of β-Lactamases. Antimicrob Agents Chemother 2017, 61, e02260-02216.
4. Bush, K.; Bradford, P. A. Interplay between β-lactamases and new β-lactamase inhibitors. Nat Rev Microbiol 2019, 17, 295-306.
5. Krajnc, A. et al. Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases. J Med Chem 2019, 62, 8544-8556.
6. Burns, C. J.; Daigle, D.; Liu, B.; McGarry, D.; Pevear, D. C.; Trout, R. E. L. Beta-Lactamase Inhibitors. WO Patent WO 2014/089365 A1.
7. Langley, G. Wet al. Profiling interactions of vaborbactam with metallo-β-lactamases. Bioorg Med Chem Lett 2019, 29, 1981-1984.

Acknowledgment: This short perspective of compound VNRX-5133 was kindly provided by Professor Chris Schofield’s group at the University of Oxford (UK).
Please contact Dr. Michael Crowder if you want us to consider your compound(s) as the MBL inhibitor of the month in the future.