The emergence and spread of pose a severe threat to public health, highlighting the urgent need for the next generation of therapeutics due to its increasing resistance to existing antibiotics. BfmR, a response regulator modulating virulence and antimicrobial resistance, shows a promising potential as a novel antimicrobial target. Developing BfmR inhibitors may propel a new therapeutic direction for intractable infection of resistant strains. In this study, we conducted a structure-based hierarchical virtual screening pipeline combining molecular docking, molecular dynamic simulation, and MM/GBSA calculation to sift the Specs chemical library and finally discover three novel potential BfmR inhibitors. The three hits can reduce the MIC of meropenem for the carbapenem-resistant (CRAB) strain ZJ06. Similar to the BfmR knockout strain, Cmp-98 was demonstrated to downregulate the expression of K locus genes, indicating it as a BfmR inhibitor. Bacteria underwent harmful morphological changes after treatment with these inhibitors. Molecular dynamic simulations found that all the hits tend to dynamically bind to different positions of the phosphorylation site of BfmR. Wherein we identified a potential inhibitory-binding cleft, beside a possible activated binding cleft at the edge of the phosphorylation site. Restraining the ligand binding poses may help exert inhibitory effects. This study reports a group of new scaffold BfmR inhibitors, offering new insights for novel antibiotic therapeutics against CRAB.