A Cephalosporin-Tripodalamine Conjugate Inhibits Metallo-β-Lactamase with High Efficacy and Low Toxicity.

The wide spread of metallo-β-lactamase (MBL)-expressing bacteria has greatly threatened human health, and there is an urgent need for inhibitors against MBLs. Herein, we present a cephalosporin-tripodalamine conjugate (DPASC) as a potent MBL inhibitor with a block-release design. The cephalosporin tag blocks the ligand binding site to reduce toxicity and is cleaved by MBLs to release active ligands to inhibit MBLs in situ . The screening of MBL-expressing pathogenic strains with 16 μg/mL DPASC showed a decrease of the minimum inhibitory concentration of meropenem (MEM) by 16 to 512-fold, and its toxicity was minimal to human HepG2 cells, with an IC 50 exceeding 512 μg/mL. An in vivo infection model with Galleria mellonella larvae showed an increased 3-day survival rate of 87% with the coadministration of DPASC and MEM, compared to 50% with MEM alone and no toxicity at a dose of 256 mg/kg of DPASC. Our findings with DPASC demonstrate that it is an effective MBL inhibitor and that the block-release strategy could be useful for the development of new MBL inhibitors.