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Discovery of taniborbactam (VNRX-5133): A broad-spectrum serine- and metallo-β-lactamase inhibitor for carbapenem-resistant bacterial infections

DOI: 10.1021/acs.jmedchem.9b01518 DOI Help

Authors: Bin Liu (VenatoRx Pharmaceuticals, Inc) , Robert E. Lee Trout (VenatoRx Pharmaceuticals, Inc) , Guo-hua Chu (VenatoRx Pharmaceuticals, Inc) , Daniel Mcgarry (VenatoRx Pharmaceuticals, Inc) , Randy W Jackson (VenatoRx Pharmaceuticals, Inc) , Jodie Hamrick (VenatoRx Pharmaceuticals, Inc) , Denis Daigle (VenatoRx Pharmaceuticals, Inc) , Susan Cusick (VenatoRx Pharmaceuticals, Inc) , Cecilia Pozzi (University of Siena) , Filomena De Luca (University of Siena) , Manuela Benvenuti (University of Siena) , Stefano Mangani (University of Siena) , Jean-denis Docquier (University of Siena) , William J. Weiss (University of North Texas Health Science Center) , Daniel C. Pevear (VenatoRx Pharmaceuticals, Inc) , Luigi Xerri (VenatoRx Pharmaceuticals, Inc) , Christopher J. Burns (VenatoRx Pharmaceuticals, Inc)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: November 2019

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.

Subject Areas: Chemistry, Biology and Bio-materials, Medicine