Discovery of Cyclic Boronic Acid QPX7728, an Ultrabroad-Spectrum Inhibitor of Serine and Metallo-β-lactamases

Despite
major advances in the β-lactamase inhibitor field,
certain enzymes remain refractory to inhibition by agents recently
introduced. Most important among these are the class B (metallo) enzyme
NDM-1 of Enterobacteriaceae and the class D (OXA) enzymes of Acinetobacter baumannii. Continuing the boronic acid program
that led to vaborbactam, efforts were directed toward expanding the
spectrum to allow treatment of a wider range of organisms. Through
key structural modifications of a bicyclic lead, stepwise gains in
spectrum of inhibition were achieved, ultimately resulting in QPX7728
(35). This compound displays a remarkably broad spectrum
of inhibition, including class B and class D enzymes, and is little
affected by porin modifications and efflux. Compound 35 is a promising agent for use in combination with a β-lactam
antibiotic for the treatment of a wide range of multidrug resistant
Gram-negative bacterial infections, by both intravenous and oral administration.