Diazabicyclooctane Functionalization for Inhibition of β‑Lactamases from Enterobacteria

Second-generation β-lactamase
inhibitors containing a diazabicyclooctane (DBO) scaffold restore
the activity of β-lactams against pathogenic bacteria, including
those producing class A, C, and D enzymes that are not susceptible
to first-generation inhibitors containing a β-lactam ring. Here,
we report optimization of a synthetic route to access triazole-containing
DBOs and biological evaluation of a series of 17 compounds for inhibition
of five β-lactamases representative of enzymes found in pathogenic
Gram-negative bacteria. A strong correlation (Spearman coefficient
of 0.87; p = 4.7 × 10–21)
was observed between the inhibition efficacy of purified β-lactamases
and the potentiation of β-lactam antibacterial activity, indicating
that DBO functionalization did not impair penetration. In comparison
to reference DBOs, avibactam and relebactam, our compounds displayed
reduced efficacy, likely due to the absence of hydrogen bonding with
a conserved asparagine residue at position 132. This was partially
compensated for by additional interactions involving certain triazole
substituents.