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

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, Jean-Denis; Weiss, W. J.; Pevear, D. C.; Xerri, L.; Burns, C. J.

doi:10.1021/acs.jmedchem.9b01518

Article (Scientific journals)

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

Liu, B.; Trout, R. E. L.; Chu, G.-H. et al.

2020 • In Journal of Medicinal Chemistry, 63 (6), p. 2789-2801

Peer Reviewed verified by ORBi

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https://hdl.handle.net/2268/252537

DOI
10.1021/acs.jmedchem.9b01518

PubMed
31765155

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Keywords :

Article; IC50; X ray crystallography; Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Borinic Acids; Carbapenems; Carboxylic Acids; Humans; Mice; Models, Molecular

Abstract :

[en] 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. Copyright © 2019 American Chemical Society.

Disciplines :

Microbiology

Author, co-author :

Liu, B.; Venatorx Pharmaceuticals Inc., 30 Spring Mill Drive, Malvern, PA 19355, United States

Trout, R. E. L.; Venatorx Pharmaceuticals Inc., 30 Spring Mill Drive, Malvern, PA 19355, United States

Chu, G.-H.; Venatorx Pharmaceuticals Inc., 30 Spring Mill Drive, Malvern, PA 19355, United States

Mcgarry, D.; Venatorx Pharmaceuticals Inc., 30 Spring Mill Drive, Malvern, PA 19355, United States

Jackson, R. W.; Venatorx Pharmaceuticals Inc., 30 Spring Mill Drive, Malvern, PA 19355, United States

Hamrick, J. C.; Venatorx Pharmaceuticals Inc., 30 Spring Mill Drive, Malvern, PA 19355, United States

Daigle, D. M.; Venatorx Pharmaceuticals Inc., 30 Spring Mill Drive, Malvern, PA 19355, United States

Cusick, S. M.; Venatorx Pharmaceuticals Inc., 30 Spring Mill Drive, Malvern, PA 19355, United States

Pozzi, C.; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, I-53100, Italy

De Luca, F.; Department of Medical Biotechnology, University of Siena, Siena, I-53100, Italy

More authors (7 more)

Language :

English

Title :

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

Publication date :

2020

Journal title :

Journal of Medicinal Chemistry

ISSN :

0022-2623

eISSN :

1520-4804

Publisher :

American Chemical Society

Volume :

Issue :

Pages :

2789-2801

Peer reviewed :

Peer Reviewed verified by ORBi

Name of the research project :

HHSN272201300019C; Award no. 360G-Wellcome-101999/Z/13/Z

Funders :

NIAID - National Institute of Allergy and Infectious Diseases [US-MD] [US-MD]
Wellcome Trust [GB]

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