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, H 2 dedpa 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. H 2 dedpa (IC 50  = 0.17 ± 0.04 μM) and compound 8 (IC 50  = 0.04 ± 0.02 μM) showed higher inhibitory activity against bla NDM-1 enzyme than the positive control ethylenediaminetetraacetic acid (EDTA, IC 50  = 28.84 ± 0.70 μM). A sterilization kinetics experiment showed that H 2 dedpain combined with MEM could kill 99.9% of bacteria within 24 h H 2 dedpa and compound 8 are therefore promising MBL inhibitors.