Hydroxamic acid with benzenesulfonamide: An effective scaffold for the development of broad-spectrum metallo-β-lactamase inhibitors

Given that β-lactam Antibiotic resistance mediated by metallo-β-lactamases (MβLs) seriously threatens human health, we designed and synthesized nineteen hydroxamic acids with benzenesulfonamide, which exhibited broad-spectrum inhibition against four tested MβLs ImiS, L1, VIM-2 and IMP-1 (except 6, 13 and 18 on IMP-1, and 18 on VIM-2), with an IC₅₀ value in the range of 0.6-9.4, 1.3-27.4, 5.4-43.7 and 5.2-49.7 µM, respectively, and restored Antibacterial activity of both cefazolin and meropenem, resulting in a 2-32-fold reduction in MIC of the Antibiotics. Compound 17 shows reversible competitive inhibition on L1 with a K_i value of 2.5 µM and significantly reduced the Bacterial load in the spleen and liver of mice infected by E. coli expressing L1. The docking studies suggest that 17 tightly binds to the Zn(Ⅱ) of VIM-2 and CphA by the oxygen atoms of sulfonamide group, but coordinates with the Zn(II) of L1 through the oxygen atoms of hydroxamic acid group. These studies reveal that the hydroxamic acids with benzenesulfonamide are the potent scaffolds for the development of MβL inhibitors.