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

ABSTRACT: A major resistance mechanism in Gram-negative bacteria is the production of ?-lactamase enzymes. Originally recognized for their ability to hydrolyze penicillins, emergent ?-lactamases can now confer resistance to other ?-lactam drugs, including both cephalosporins and carbapenems. The emergence and global spread of ?-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-?-lactamase enzymes. Lead optimization, beginning with narrower-spectrum, weakly active compounds, provided 20 (VNRX-5133, taniborbactam), a boronic-acid-containing pan-spectrum ?-lactamase inhibitor. In vitro and in vivo studies demonstrated that 20 restored the activity of ?-lactam antibiotics against carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum ?-lactamase inhibitor to enter clinical development.

SUBMITTER: Liu B 

PROVIDER: S-EPMC7104248 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature