Novel methyldithiocarbazate derivatives as NDM-1 inhibitors to combat multidrug-resistant bacterial infection with β-lactams.

Given the ever-evolving landscape of antimicrobial resistance, the emergence of New Delhi metallo-β-lactamase-1 (NDM-1) has introduced a formidable challenge to global public health. In previous research, we identified the Compound Zndm19 as an NDM-1 inhibitor and reported Zndm19 derivatives, which exhibited moderate antibacterial activity when combined with meropenem (MEM). This moderate activity may have been due to the inability of Zndm19 to efficiently penetrate the bacterial outer membrane or its susceptibility to hydrolysis, which prevented it from exerting strong enzyme inhibition in synergy with bacterial cells. In this study, we aimed to overcome these limitations by employing a scaffold hopping strategy, abandoning the original core structure. We designed and synthesized 21 compounds and discovered that Compound A8 could effectively restore the antibacterial activity of MEM against NDM-1-positive Escherichia coli (E. coli). Compound A8 restored the ability of MEM to penetrate the cell wall of gram-negative bacteria, leading to oxidative stress-induced disarray within bacterial cells. This disruption ultimately led to the impairment of bacterial cell membrane integrity and permeability, consequently amplifying the synergistic antimicrobial efficacy of the combined treatment. Furthermore, compared with Zndm19, Compound A8 demonstrated broader therapeutic applications in the Galleria mellonella infection model and the murine peritonitis infection model. Molecular docking, site-directed mutagenesis, and fluorescence quenching assays confirmed that Compound A8 could directly interact with NDM-1, thereby further inhibiting its hydrolytic activity. These findings elucidate the antimicrobial mechanism of novel methyl dithiocarbamate derivatives and provide new insights for the development of new NDM-1 inhibitors.