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 <b>11</b>, discovered earlier as <i>B. fragilis</i> metallo-beta-lactamase inhibitors, was selected for <i>in silico</i> virtual screening. From these efforts, compound <b>12</b> 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 <b>23</b> with a pan MBL inhibition profile. In <i>in vivo</i> studies, compound <b>23</b> 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.