Diazabicyclooctane Functionalization For Inhibition Of Beta-Lactamases From Enterobacteria

Second-generation beta-lactamase inhibitors containing a diazabicyclooctane (DBO) scaffold restore the activity of beta-lactams against pathogenic bacteria, including those producing class A, C, and D enzymes that are not susceptible to first-generation inhibitors containing a beta-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 beta-lactamases representative of enzymes found in pathogenic Gram-negative bacteria. A strong correlation (Spearman coefficient of 0.87; p = 4.7 x 10(-21)) was observed between the inhibition efficacy of purified beta-lactamases and the potentiation of beta-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.