| Autor: |
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. |
| Zdroj: |
Journal of Medicinal Chemistry; March 2020, Vol. 63 Issue: 6 p2789-2801, 13p |
| Abstrakt: |
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 20restored the activity of β-lactam antibiotics against carbapenem-resistant Pseudomonas aeruginosaand carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum β-lactamase inhibitor to enter clinical development. |
| Databáze: |
Supplemental Index |
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