TY - JOUR
T1 - Discovery of Taniborbactam (VNRX-5133)
T2 - A Broad-Spectrum Serine- And Metallo-β-lactamase Inhibitor for Carbapenem-Resistant Bacterial Infections
AU - Liu, Bin
AU - Trout, Robert E.Lee
AU - Chu, Guo Hua
AU - Mcgarry, Daniel
AU - Jackson, Randy W.
AU - Hamrick, Jodie C.
AU - Daigle, Denis M.
AU - Cusick, Susan M.
AU - Pozzi, Cecilia
AU - De Luca, Filomena
AU - Benvenuti, Manuela
AU - Mangani, Stefano
AU - Docquier, Jean Denis
AU - Weiss, William J.
AU - Pevear, Daniel C.
AU - Xerri, Luigi
AU - Burns, Christopher J.
N1 - Funding Information:
This project has been funded in whole or in part from the National Institute for Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN272201300019C and the Wellcome Trust under award no. 360G-Wellcome-101999/Z/13/Z. We thank Cassandra Chatwin and Kaitlyn John for generating MIC data. We thank Dr. Stephen M. Condon for helpful discussions and the review of this manuscript.
Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2020/3/26
Y1 - 2020/3/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85077130672&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.9b01518
DO - 10.1021/acs.jmedchem.9b01518
M3 - Article
C2 - 31765155
AN - SCOPUS:85077130672
SN - 0022-2623
VL - 63
SP - 2789
EP - 2801
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 6
ER -