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

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