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Metallo-β-lactamase (MβL) ImiS contributes to the emergence of carbapenem resistance. A potent scaffold, meta-substituted benzenesulfonamide, was constructed and assayed against MβLs. The twenty-one obtained molecules specifically inhibited ImiS (IC50= 0.11–9.3 μM); 2gwas found to be the best inhibitor (IC50= 0.11 μM), and 1gand 2gexhibited partially mixed inhibition with Kiof 8.0 and 0.55 μM. The analysis of the structure–activity relationship revealed that the meta-substitutes improved the inhibitory activity of the inhibitors. Isothermal titration calorimetry (ITC) assays showed that 2greversibly inhibited ImiS. The benzenesulfonamides exhibited synergistic antibacterial effects against E. coliBL21 (DE3) cells with ImiS, resulting in a 2–4-fold reduction in the MIC of imipenem and meropenem. Also, mouse experiments showed that 2ghad synergistic efficacy with meropenem and significantly reduced the bacterial load in the spleen and liver after a single intraperitoneal dose. Tracing the ImiS in living E. colicells by RSat a super-resolution level (3D-SIM) showed that the target was initially associated on the surface of the cells, then there was a high density of uniform localization distributed in the cytosol of cells, and it finally accumulated in the formation of inclusion bodies at the cell poles. Docking studies suggested that the sulfonamide group acted as a zinc-binding group to coordinate with Zn(ii) and the residual amino acid within the CphA active center, tightly anchoring the inhibitor at the active site. This study provides a highly promising scaffold for the development of inhibitors of ImiS, even the B2 subclasses of MβLs.