Rapid Evolution of a Fragment-like Molecule to Pan-Metallo-Beta-Lactamase Inhibitors: Initial Leads toward Clinical Candidates

With
the emergence and rapid spreading of NDM-1 and existence of
clinically relevant VIM-1 and IMP-1, discovery of pan inhibitors targeting
metallo-beta-lactamases (MBLs) became critical in our battle against
bacterial infection. Concurrent with our fragment and high-throughput
screenings, we performed a knowledge-based search of known metallo-beta-lactamase
inhibitors (MBLIs) to identify starting points for early engagement
of medicinal chemistry. A class of compounds exemplified by 11, discovered earlier as B. fragilis metallo-beta-lactamase inhibitors, was selected for in silico virtual screening. From these efforts, compound 12 was
identified with activity against NDM-1 only. Initial exploration on
metal binding design followed by structure-guided optimization led
to the discovery of a series of compounds represented by 23 with a pan MBL inhibition profile. In in vivo studies,
compound 23 in combination with imipenem (IPM) robustly
lowered the bacterial burden in a murine infection model and became
the lead for the invention of MBLI clinical candidates.