H₂depda: An acyclic adjuvant potentiates meropenem activity in vitro against metallo-β-lactamase-producing enterobacterales

Metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) pose an emerging threat to public health worldwide. An effective inhibitor of MBLs is therefore urgently needed for clinical use. In this study, two acyclic pyridine-containing ligands, H₂dedpa and compound 8, were discovered with excellent activities when combined with meropenem (MEM) against MBL (bla_NDM and bla_IMP)-producing clinical isolates, including Escherichia coli, Citrobacter freundii, Proteus mirabilis, Enterobacter cloacae and Klebsiella pneumoniae. In particular, these two compounds improved the activity of MEM against E. coli harboring the bla_NDM-4 gene by nearly 40,960 times. H₂dedpa (IC₅₀ = 0.17 ± 0.04 μM) and compound 8 (IC₅₀ = 0.04 ± 0.02 μM) showed higher inhibitory activity against bla_NDM-1 enzyme than the positive control ethylenediaminetetraacetic acid (EDTA, IC₅₀ = 28.84 ± 0.70 μM). A sterilization kinetics experiment showed that H₂dedpain combined with MEM could kill 99.9% of bacteria within 24 h H₂dedpa and compound 8 are therefore promising MBL inhibitors.