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The research focuses on the design, synthesis, and evaluation of ebselen derivatives as potential inhibitors of New Delhi-β-lactamase-1 (NDM-1) producing bacteria. These derivatives showed significant synergistic antibacterial activity against carbapenem-resistant enterobacteriaceae isolates, with low cytotoxicity and the ability to covalently bind to NDM-1 enzyme. The study suggests that compound A4 is a potent NDM-1 inhibitor and may serve as a lead compound for drug development in resistant bacteria.
New Delhi-β-lactamase-1 (NDM-1) is a type of one of metal-β-lactamase. NDM-1-expressing bacteria can spread rapidly across the globe via plasmid transfer, which greatly undermines the clinical efficacy of the last of the carbapenem class of antibiotics. Research on NDM-1 inhibitors has attracted extensive attention. However, there are currently no clinically available NDM-1 inhibitors. Our research group has reported that 1,2-benzisoselenazol-3(2H)-one derivatives as covalent NDM-1 inhibitors can restore the efficacy of Meropenem（Mem） against NDM-1 producing strains. In this study, 22 compounds were designed and synthesized, which restored the Mem susceptibility of NDM-1-expressing Escherichia coli. and its minimum inhibitory concentration (MIC) was reduced by 2-16 times. Representative compound A4 showed significant synergistic antibacterial activity against NDM-1-producing carbapenem-resistant enterobacteriaceae (CRE) isolates. In vitro, NDM-1 enzyme inhibitory activity test showed that IC50 was 1.26 ± 0.37 μM, which had low cytotoxicity. When combined with meropenem, it showed good combined antibacterial activity. Electrospray ionization mass spectrometry (ESI-MS) analysis demonstrates that compound A4 covalently binds to NDM-1 enzyme. In summary, compound A4 is a potent NDM-1 covalent inhibitor and provides a potential lead compound for drug development in resistant bacteria.
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