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

  • J Med Chem. 2020 Mar 26;63(6):2789-2801. doi: 10.1021/acs.jmedchem.9b01518.
Bin Liu  1 ,  Robert E Lee Trout  1 ,  Guo-Hua Chu  1 ,  Daniel McGarry  1 ,  Randy W Jackson  1 ,  Jodie C Hamrick  1 ,  Denis M Daigle  1 ,  Susan M Cusick  1 ,  Cecilia Pozzi  2 ,  Filomena De Luca  3 ,  Manuela Benvenuti  2 ,  Stefano Mangani  2 ,  Jean-Denis Docquier  3 ,  William J Weiss  4 ,  Daniel C Pevear  1 ,  Luigi Xerri  1 ,  Christopher J Burns  1
Affiliations
  • 1. Venatorx Pharmaceuticals, Inc., 30 Spring Mill Drive, Malvern, Pennsylvania 19355, United States.
  • 2. Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy.
  • 3. Department of Medical Biotechnology, University of Siena, I-53100 Siena, Italy.
  • 4. UNT System College of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, Texas 76107-2699, United States.
PMID: 31765155 DOI: 10.1021/acs.jmedchem.9b01518
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.

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