Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2020-03, Vol.63 (6), p.2789-2801

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.