Systematic research of H2dedpa derivatives as potent inhibitors of New Delhi Metallo-β-lactamase-1

Abstract

New Delhi Metallo-β-lactamase-1 (NDM-1), a Zn (II)-dependent enzyme, can catalyze the hydrolysis of almost all β-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.

Keywords: Antibiotic resistance; Enterobacteriaceae; Metallo-β-lactamase inhibitor; New Delhi Metallo-β-lactamase-1; Picolinic acid.