Discovery of Taniborbactam (VNRX-5133): A Broad-Spectrum Serine- And Metallo-β-lactamase Inhibitor for Carbapenem-Resistant Bacterial Infections

Bin Liu, Robert E.Lee Trout, Guo Hua Chu, Daniel Mcgarry, Randy W. Jackson, Jodie C. Hamrick, Denis M. Daigle, Susan M. Cusick, Cecilia Pozzi, Filomena De Luca, Manuela Benvenuti, Stefano Mangani, Jean Denis Docquier, William J. Weiss, Daniel C. Pevear, Luigi Xerri, Christopher J. Burns

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

A major resistance mechanism in Gram-negative bacteria is the production of β-lactamase enzymes. Originally recognized for their ability to hydrolyze penicillins, emergent β-lactamases can now confer resistance to other β-lactam drugs, including both cephalosporins and carbapenems. The emergence and global spread of β-lactamase-producing multi-drug-resistant "superbugs" has caused increased alarm within the medical community due to the high mortality rate associated with these difficult-to-treat bacterial infections. To address this unmet medical need, we initiated an iterative program combining medicinal chemistry, structural biology, biochemical testing, and microbiological profiling to identify broad-spectrum inhibitors of both serine- and metallo-β-lactamase enzymes. Lead optimization, beginning with narrower-spectrum, weakly active compounds, provided 20 (VNRX-5133, taniborbactam), a boronic-acid-containing pan-spectrum β-lactamase inhibitor. In vitro and in vivo studies demonstrated that 20 restored the activity of β-lactam antibiotics against carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum β-lactamase inhibitor to enter clinical development.

Original languageEnglish
Pages (from-to)2789-2801
Number of pages13
JournalJournal of Medicinal Chemistry
Volume63
Issue number6
DOIs
StatePublished - 26 Mar 2020

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    Liu, B., Trout, R. E. L., Chu, G. H., Mcgarry, D., Jackson, R. W., Hamrick, J. C., Daigle, D. M., Cusick, S. M., Pozzi, C., De Luca, F., Benvenuti, M., Mangani, S., Docquier, J. D., Weiss, W. J., Pevear, D. C., Xerri, L., & Burns, C. J. (2020). Discovery of Taniborbactam (VNRX-5133): A Broad-Spectrum Serine- And Metallo-β-lactamase Inhibitor for Carbapenem-Resistant Bacterial Infections. Journal of Medicinal Chemistry, 63(6), 2789-2801. https://doi.org/10.1021/acs.jmedchem.9b01518