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 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.