RESUMEN
New Delhi Metallo-ß-lactamase-1 (NDM-1), a Zn (II)-dependent enzyme, can catalyze the hydrolysis of almost all ß-lactam antibiotics including carbapenems, resulting in bacterial antibiotic resistance, which threatens public health globally. Based on our finding that H2dedpa is as an efficient NDM-1 inhibitor, a series of H2dedpa derivatives was systematically prepared. These compounds exhibited significant activity against NDM-1, with IC50 values 0.06-0.94 µM. In vitro, compounds 6k and 6n could restore the activity of meropenem against Klebsiella pneumoniae, Escherichia coli and Proteus mirabilis possessing either NDM or IMP. In particular, the activity of meropenem against E. coli producing NDM-4 could be improved up to 5333 times when these two compounds were used. Time-kill cell-based assays showed that 99.9% of P. mirabilis were killed when treated with meropenem in combination with compound 6k or 6n. Furthermore, compounds 6k and 6n were nonhemolytic (HC50 > 1280 µg/mL) and showed low toxicity toward mammalian (HeLa) cells. Mechanistic studies indicated that compounds 6k and 6n inhibit NDM-1 by chelating the Zn2+ ion of the enzyme.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Etilaminas/farmacología , Piridinas/farmacología , beta-Lactamasas/efectos de los fármacos , Antibacterianos/farmacología , Etilaminas/química , Células HeLa , Hemólisis/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Piridinas/químicaRESUMEN
Metallo-ß-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 (blaNDM and blaIMP)-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 blaNDM-4 gene by nearly 40,960 times. H2dedpa (IC50â¯=â¯0.17⯱â¯0.04⯵M) and compound 8 (IC50â¯=â¯0.04⯱â¯0.02⯵M) showed higher inhibitory activity against blaNDM-1 enzyme than the positive control ethylenediaminetetraacetic acid (EDTA, IC50â¯=â¯28.84⯱â¯0.70⯵M). A sterilization kinetics experiment showed that H2dedpain combined with MEM could kill 99.9% of bacteria within 24â¯h H2dedpa and compound 8 are therefore promising MBL inhibitors.