3-Bromopyruvate as a potent covalently reversible inhibitor of New Delhi metallo-β-lactamase-1 (NDM-1).

The bacteria, harboring metallo-β-lactamases (MβLs), become resistant on most β-lactam antibiotics, specifically New Delhi metallo-β-lactamase-1 (NDM-1), which hydrolyzes almost all β-lactam antibiotics leading to bacterial multiple-drug resistance. It is highly desirable to develop effective NDM-1 inhibitors in reviving the efficacy of existing antibiotics. Here, we report a potent covalently reversible scaffold, 3-Bromopyruvate (3BP) to target the NDM-1 in vitro and in vivo. Enzymatic kinetic studies revealed that 3BP is capable of inhibiting the B1 and B2 MβLs and exhibited the best inhibition on NDM-1 with an IC50 of 2.57 μM, also, it was found to be a dose- and time-dependent inhibitor. The study of inhibition mechanism suggested that 3BP reversibly inactivate NDM-1, and may form a dynamic reversible covalent bond with cysteine at active site of the enzyme. Besides, 3BP effectively restored the activity of five β-lactam antibiotics on three clinical strains expressing NDM-1, resulting in 2-8-fold reduction in MIC. Moreover, the toxicity evaluation of 3BP against L929 mouse fibroblastic cells indicated that 3BP had low cytotoxicity, implying it may be used as lead molecule for future drug candidate.