Systematic research of H2dedpa derivatives as potent inhibitors of New Delhi Metallo-β-lactamase-1
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 H 2 dedpa is as an efficient NDM-1 inhibitor, a series of H 2 dedpa derivatives was systematically prepared. These compounds exhibited significant activity against NDM-1, with IC 50 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 (HC 50 > 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 Zn 2+ ion of the enzyme.
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